Use of NK-1 receptor antagonist serlopitant in pruritus

ABSTRACT

The invention relates to methods for treating pruritus with NK-1 receptor antagonists such as serlopitant. The invention further relates to pharmaceutical compositions comprising NK-1 receptor antagonists such as serlopitant. In addition, the invention encompasses treatment of a pruritus-associated condition with serlopitant and an additional antipruritic agent, and the use of serlopitant as a sleep aid, optionally in combination with an additional sleep-aiding agent.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation of U.S. patent applicationSer. No. 15/626,001 filed Jun. 16, 2017, which is a Continuation of U.S.patent application Ser. No. 15/269,792 filed Sep. 19, 2016, now U.S.Pat. No. 9,737,507, which is a Continuation of U.S. patent applicationSer. No. 14/899,255 filed Dec. 17, 2015, now U.S. Pat. No. 9,486,439,which is a U.S. National Phase application under 35 U.S.C. § 371 ofInternational Application No. PCT/US14/43811 filed Jun. 24, 2014, whichis a Continuation in Part of U.S. patent application Ser. No. 13/925,509filed Jun. 24, 2013, now U.S. Pat. No. 8,906,951, and claims priority toand benefit of U.S. Provisional Patent Application No. 61/838,784, filedJun. 24, 2013, the disclosures of which are herein incorporated byreference in their entirety.

TECHNICAL FIELD

The invention relates to methods for treating acute or chronic prurituswith an NK-1 receptor antagonist. The invention further relates topharmaceutical compositions comprising an NK-1 receptor antagonist.

BACKGROUND OF THE INVENTION

Pruritus, or itch, is an uncomfortable skin sensation that provokes adesire to scratch. Although itch may be acute, for example, from aninsect sting, chronic pruritus originates from many different causes. Itis a seriously debilitating condition, comparable to chronic pain, whichnegatively impacts quality of life.

Chronic pruritus affects millions of people worldwide, although solidepidemiological data is very limited. For example, one study reportedthat 8-10% of the population of Oslo suffer from chronic pruritus fromall causes (F. Dalgard et al., J. Investig. Dermatol. Symp. Proc., 2004,9(2):120-5). Patients with certain diseases and conditions report highincidences of chronic itch, including those with psoriasis (78-84%),Hodgkin's disease (25-35%), dialysis patients (22%), and polycythaemicavera (48%) (M. Metz and S. Ständer, CME Dematol., 2008; 3(3):124-143).Chronic pruritus is also a prevalent symptom in cutaneous T-celllymphoma (68-93%), a disease that includes mycosis fungoides and Sézarysyndrome (N. Meyer et al., Acta Derm. Venereol., 2010, 90:12-17).Pruritus is the most common dermatological complaint in elderly patients(S. Beauregard and B. A. Gilchrest, Arch. Dermatol., 1987, 123:1638-43).Itch is often the side effect of certain drugs, such as EGF receptorantagonists.

Antihistamines can sometimes effectively treat itch due to acuteurticaria, but many chronic pruritic diseases respond poorly toconventional H1 receptor antagonists (Tey H. L. and G. Yosipovitch; Br.J. Dermatol., 2011, 166(1):5-17). In addition to marginal efficacy,antihistamines can also cause intolerable drowsiness. Other currenttherapies possess various limitations. For example, anticonvulsants suchas gabapentin inhibit spinal mechanisms in the perception of itch, buttheir use is limited due to their slow onset of action (5-6 weeks) (Metzand Ständer, 2008). Opiate receptor antagonists such as naloxone,nalmefene, and naltrexone decreased pruritus symptoms in patients withliver and kidney disease, although significant central nervous andgastrointestinal side effects occurred (Metz and Ständer, 2008; N. V.Bergasa et al., Hepatology, 2006, 44(5):1317-23).

Substance P, the endogenous ligand for the neurokin-1 (NK-1) receptor,is a significant mediator of pruritus (T. Andoh et al., J. Pharmacol.Exp. Ther., 1998, 286:1140-5). Intradermal injection of substance Pelicits an itch sensation in human subjects, and an associated itchresponse in mice. The substance P-induced itch-associated response inmice is not inhibited by antihistamines (B. Amatya et al., SkinPharmacol. Physiol., 2010; 23:133-138; C. Weidner et al., J. Invest.Dermatol., 2000, 115:1015-1020). In an experiment designed to study therole of substance P in pruritus, Ohmura et al. reported that tachykininNK-1 receptor antagonist, BIIF 1149 CL, inhibited scratching behavior ina picrylchloride-induced dermatitis model in NC/Nga mice (Eur. J.Pharmacol., 2004, 491:191-194; U.S. Patent Application No. 2003/100565).

Aprepitant (Emend®), an NK-1 receptor antagonist, is approved by the FDAfor use in the prevention of chemically induced nausea and vomiting(emesis) after chemotherapy. Duval and Dubertret first reported thatoral aprepitant (80 mg daily) had utility in treating pruritus in threepatients with Sézary syndrome (N. Engl. J. Med., 2009, 381(14):1415-6).Torres et al. disclosed similar results (J. Am. Acad. Dermatol., 2012;66(1):e14-5). Ständer et al. conducted a small, open-label study whichdemonstrated that aprepitant significantly decreased chronic prurituscaused by conditions such as atopic diathesis and prurigo nodularis. Inthis study, twenty previously untreatable patients were given a dailydose of 80 mg for 3 to 13 days. Eighty percent of the patientsexperienced a considerable reduction in itch intensity (S. Ständer, etal., PLoS One, 2010, 5:6, e10968). However, Wallengren conducted afollow-up double-blind study based on Ständer's work testing a singledose of topical aprepitant blended at a 5% concentration in a lipophilicvehicle in patients suffering from chronic pruritus of variousetiologies. Although the drug was absorbed into the skin, the patients'itch was not alleviated (J. Wallengren, Arch. Dermatol., 2012,148(8):967-9).

Although oral aprepitant is generally well-tolerated, it is extremelyexpensive, limiting its use in chronic pruritus (Tey, 2011). Further,aprepitant is a moderate inhibitor as well as an inducer of CYP3A4 andCYP2C9, indicating that drug-drug interactions with chemotherapeuticagents and corticoteroids must be considered (Torres, 2012). Mir andCoriat have suggested that the risk of drug-drug interactions withaprepitant is high because it can alter the activity of cytochrome P4503A4 isoform (CYP-3A4), an enzyme involved in the metabolism of a rangeof commonly prescribed drugs, including tyrosine-kinase inhibitors,either inducing or inhibiting the CYP-3A4, depending on which drugs aregiven concomitantly. Tyrosine-kinase inhibitors do not induce frequentnausea and emesis; therefore, clinical experience with concomitantadministration of aprepitant and these drugs is scarce. Furthermore, thepharmacokinetics of tyrosine-kinase inhibitors varies widely betweenpatients, and drug-drug interactions are common (O. Mir and R. Coriat,The Lancet, 2012, 13:964-965). Thus, the need for additional, safetreatments for acute and chronic pruritus exists.

SUMMARY OF THE INVENTION

In one aspect, this invention provides a method of treating pruritus ina patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of3-[(3aR,4R,5S,7aS)-5-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl)cyclopent-2-en-1-oneor a pharmaceutically acceptable salt, solvate or polymorph thereof. Inone embodiment, the therapeutically effective amount comprises a dosageof 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25mg, or 30 mg one or more times a day. In another embodiment, thetherapeutically effective amount comprises a dosage of 0.25 mg, 1 mg, or5 mg once a day. In a further embodiment, the therapeutically effectiveamount comprises a dosage of from about 0.1 mg to about 30 mg or fromabout 1 mg to about 7.5 mg. In another embodiment, the therapeuticallyeffective amount is administered orally in the form of a tablet. In afurther embodiment, the therapeutically effective amount is administeredonce a day at bedtime. In another embodiment, the therapeuticallyeffective amount is administered once a day, once every other day, onceevery third day, once every fourth day, or once a week. In otherembodiments, serlopitant is administered under a chronic dosing regimen.In some embodiments, a therapeutically effective amount of serlopitantis administered over a period of at least 2 weeks, 3 weeks, 1 month, 1.5months, 2 months, 3 months, 4 months, 5 months, 6 months or longer.

In another aspect, this invention provides a method of treating prurituswhereby3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-one(serlopitant) or a pharmaceutically acceptable salt, solvate orpolymorph thereof is administered to a patient in need of such treatmentaccording to a schedule, wherein a least one loading dose is firstadministered, and, second, at least one therapeutically effectmaintenance dose is administered. In one embodiment, the loading dose isfive times, four times, three times, or two times the maintenance dose.In another embodiment, the loading dose is three times the maintenancedose. In a further embodiment, the loading dose is administered on day 1and the maintenance dose is administered on day 2 and thereafter. Inanother embodiment, the loading dose and the maintenance dose areadministered at bedtime. In another embodiment, the method furthercomprises administering a second loading dose prior to administering themaintenance dose. In one embodiment, the loading dose is three times themaintenance dose and the second loading dose is two times themaintenance dose. In a further embodiment, the therapeutically effectivemaintenance dose is 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg,1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15mg, 20 mg, 25 mg, or 30 mg administered one or more times a day. Inanother embodiment, the therapeutically effective maintenance dosecomprises a dosage of 0.25 mg, 1 mg, or 5 mg administered once a day. Ina further embodiment, the therapeutically effective maintenance dosecomprises a dosage from about 0.1 mg to about 30 mg or from about 1 mgto about 7.5 mg. In another embodiment, the therapeutically effectivemaintenance dose is administered once a day, once every other day, onceevery third day, once every fourth day, or once a week. In otherembodiments, serlopitant is administered under a chronic dosing regimen.In some embodiments, a therapeutically effective maintenance dose ofserlopitant is administered over a period of at least 2 weeks, 3 weeks,1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months orlonger. In certain embodiments, serlopitant is administered orally.

In one aspect, this invention provides a pharmaceutical composition forthe treatment of pruritus comprising3-[(3aR,4R,5S,7aS)-5[(1R)-1-(3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-ylcyclopent-2-en-1-oneor a pharmaceutically acceptable salt, solvate or polymorph thereof anda pharmaceutically acceptable carrier. In one embodiment, thepharmaceutical composition is formulated as a tablet comprising Compound1 or a pharmaceutically acceptable salt, solvate or polymorph thereofand one or more diluents, disintegrants, surfactants or lubricants. Inanother embodiment, the composition comprises a capsule filled with asolution comprising Compound 1 or a pharmaceutically acceptable salt,solvate or polymorph thereof and an amphiphilic agent. In a furtherembodiment, the amphiphilic agent is a fatty add ester of glycerol,propylene glycol or sorbitol. In another embodiment, the pharmaceuticalcomposition comprises 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,15 mg, 20 mg, 25 mg, or 30 mg of Compound 1 or a pharmaceuticallyacceptable salt, solvate or polymorph thereof. In another embodiment,the composition comprises 0.25 mg, 1 mg, or 5 mg of Compound 1 or apharmaceutically acceptable salt, solvate or polymorph thereof.

In another aspect, this invention provides a method of treating acute orchronic pruritus in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of apharmaceutical composition comprising3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-oneor a pharmaceutically acceptable salt, solvate or polymorph thereof anda pharmaceutically acceptable carrier. In one embodiment, the methodinvolves treatment with a pharmaceutical composition formulated as atablet comprising Compound 1 or a pharmaceutically acceptable salt,solvate or polymorph thereof and one or more diluents, disintegrants,surfactants or lubricants. In another embodiment, the method involvesadministration of a composition comprising a capsule filled with asolution comprising Compound 1 or a pharmaceutically acceptable salt,solvate or polymorph thereof and an amphiphilic agent. In a furtherembodiment, the amphiphilic agent is a fatty acid ester of glycerol,propylene glycol or sorbitol. In another embodiment, the method involvestreatment with a pharmaceutical composition comprising 0.10 mg, 0.15 mg,0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg,8 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of Compound1 or a pharmaceutically acceptable salt, solvate or polymorph thereof.In another embodiment, the composition comprises 0.25 mg, 1 mg, or 5 mgof Compound 1 or a pharmaceutically acceptable salt, solvate orpolymorph thereof.

In a further embodiment, a pruritus-associated condition is treated byadministration of serlopitant (Compound 1) and an additionalantipruritic agent. In a still further embodiment, a sleep problem ordisorder is treated by administration of serlopitant, optionally incombination with an additional seep-aiding agent.

Other objects of the invention may be apparent to one skilled in the artupon reading the following specfication and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 depicts a synthetic scheme for serlopitant, Compound 1.

FIG. 2 illustrates a Franz diffusion cell for studying skin permeationof a drug in vitro.

FIG. 3 shows the cumulative release of serlopitant from topicalformulations B and C into the receptor chamber of a Franz diffusion cellat various time points in an in vitro study of skin permeation.

FIG. 4 shows the amount of serlopitant (called “VPD737”) retained in theskin at the end of the Franz diffusion cell study. Each bar representsug of serlopitant/g of skin in 250 um skin layers. For each of topicalformulations B and C, the bars from left to right represent the amountof serlopitant retained in skin layers from the stratum corneum to thedermis.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, al technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. It must be noted that as usedherein and in the appended claims, the singular forms “a”, “and”, and“the” include plural referents unless the context clearly dictatesotherwise.

Reference will now be made in detail to certain preferred methods oftreatment, compounds and methods of administering these compounds. Theinvention is not limited to those preferred compounds and methods, butrather is defined by the claim(s) issuing herefrom.

Introduction

Serlopitant is a neurokinin-1 (NK-1) receptor antagonist. The presentinvention provides a method for treating chronic pruritus and relatedconditions using serlopitant or a pharmaceutically acceptable salt orhydrate thereof. Chemically, the generic name serlopitant refers to thecompound of Compound 1:

The I.U.P.A.C. name for the compound is3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-one.Alternatively, Compound 1 may be named3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one.For purposes of the present invention, it is understood that any ofthese designations for Compound 1 may be interchangeably used and havethe same meaning. It is further understood that the invention alsoencompasses the racemic form of serlopitant (Compound 1).

Serlopitant has previously been disclosed as a neurokinin-1 (NK-1)receptor antagonist, an inhibitor of tachykinin and, in particular, ofsubstance P (J. Jiang, et al., J. Med. Chem., 2009, 52:3039-3046)).Neurokinin receptors are part of the larger family of G-protein coupledreceptors that elicit many of their effects via activation of theinositol phosphate signal transduction pathway. NK-1 receptors arepresent in both the central and peripheral nervous system and invascular endothelial cells, muscle and cells of the immune system.Compound 1 is unusually selective (>39,000 fold) for the cloned humanNK-1 receptor over the cloned human NK-2 and NK-3 receptors, asdemonstrated using Chinese hamster ovary cells stably expressing therespective receptors (Jiang et al., 2009). Jiang et al. showed thatserlopitant binds to the human NK-1 receptor with a K_(d) of 46 pM andthat it displaces substance P binding at the same receptor with an IC₅₀of 61 pM.

Compound 1 is a weak reversible inhibitor of human CYP-3A4, 2C8, 2C9,2C19, 2D6, and 1A2 enzymes, the IC₅₀ values of which are 39, 58, 30, 29,35, and >100 pM, respectively. Serlopitant did not significantly induceCYP-3A4 mRNA in three individual preparations of human hepatocytes.These data suggest that serlopitant will have minimal drug-druginteraction liability in humans and that any drug-drug interactions willbe reduced in comparison with other NK-1 receptor antagonists. Althoughbroad-based counter-screening of serlopitant in more than 145 assaysidentified a number of weak activities between 1 and 10 pM, no assaysfor which IC₅₀<1 pM were observed. Therefore, off-target activities weremore than 20000-fold less potent than hNK-1 activity (Jiang et al.,2009).

It has been suggested serlopitant and its analogs would be useful in theprevention and treatment of a variety of clinical conditionscharacterized by the presence of an excess of tachykinin, in particularsubstance P, activity. Serlopitant has been disclosed as a treatment foremesis and for urinary incontinence (U.S. Pat. Nos. 7,217,731,7,345,083, 7,544,815, 7,645,790, and 7,893,091, the disclosures of whichare herein incorporated by reference; U.S. Published Application Nos. US2009/0270477, US 2010/0113469, and US 2010/0209496, the disclosures ofwhich are herein incorporated by reference; and PCT Publication WO2007/146224, the disclosure of which is herein incorporated byreference).

The safety and tolerability of serlopitant have been evaluated inseveral human clinical trials for the treatment or prevention of withoveractive bladder (OAB). In one investigation, a total of 557 patientswith OAB were randomized into this double-blind, placebo-controlled andactive-controlled (tolterodine), dose-ranging study. Serlopitant at 0.25and 4 mg daily significantly reduced the number of daily micturitionscompared with placebo. There were no drug-related serious adverseexperiences and the drug was generally well tolerated. However,serlopitant did not show a dose response relationship with micturitionfrequency, and did not significantly influence the secondary efficacyend points of urinary urgency, urge incontinence and total incontinence.Tolterodine was numerically more effective than serlopitant at allefficacy end points and statistically significantly more effective thanplacebo. Serlopitant was not associated with the adverse experience ofdry mouth common in patients receiving tolterodine, a muscarinicantagonist. (See: Frenkl, T. L. et al., J. Urology, 2009, 181(4), Suppl.8, p. 876; Frenkl, T. L. et al., Neurourol. Urodyn., 2009,28(2):143-144; Frenkl, T. L. et al., European Urology Supplements, 2009,8(4):134; Frenkl, Tara L, et al., J. Urology, 2010, 184(2):616-622.)

Chemical Description of Serlopitant

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. When the compound of thepresent invention is basic, salts may be prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, ethanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of the present invention are meant to also include thepharmaceutically acceptable salts.

The term “solvate” refers to an aggregate that consists of a solute ionor molecule with one or more solvent molecules. “Solvates” includehydrates, that is, aggregates of a compound of interest with water. Itwill be understood that, as used herein, references to the compounds ofthe present invention are meant to also include the solvates.

The term “polymorph” refers to a crystalline form of a compound that cancrystallize in different forms. The invention also encompassespolymorphs of serlopitant. Examples of polymorphs of serlopitant includewithout limitation anhydrous crystalline Forms I and II of free baseserlopitant as disclosed in US Pat. App. Pub. No. 2009/0270477 to Kuetheet al. Form I is characterized by diffraction peaks obtained from X-raypowder diffraction pattern corresponding to d-spacings of 10.4, 9.9,9.2, 5.5, 5.0, 4.1, 3.9, 3.6 and 3.5 angstroms. Form II is characterizedby diffraction peaks obtained from X-ray powder diffraction patterncorresponding to d-spacings of 7.7, 5.3, 4.9, 4.8, 4.6, 4.2, 3.9, 3.8and 2.8 angstroms. US 2009/0270477 is incorporated herein by referencein its entirety.

Chemical Synthesis.

Serlopitant may be prepared as described by Jiang et al. (J. Med. Chem.2009, 52:3039-3046), which is herein incorporated by reference in itsentirety. Alternatively, the method of Kuethe et al., as described inU.S. Pat. No. 7,544,815, or Bunda et al., as described in U.S. Pat. No.7,217,731, both of which are herein incorporated by reference in theirentirety, may be used.

The method of Kuethe et al. is depicted in FIG. 1. Briefly, commerciallyavailable 4-fluorophenylacetic acid (2) (Sigma-Aldrich Co. LLC, St.Louis, Mo.) is reacted with thionyl chloride in DMF/toluene to yieldacid chloride (3). The acid chloride (3) is then reacted with thehydrochloride salt of the Weinreb amine (CH₃NHOCH₃.HCl) in the presenceof sodium hydroxide to give2-(4-fluorophenyl)-N-methoxy-N-methylacetamide (4). A vinyl Grignardreaction converts (4) to 1-(4-fluorophenyl)but-3-en-2-one (5). TESdienyl ether (6) is produced from the reaction of (2) withchlorotriethylsilane (TESCl) in the presence of iPr₂NEt₂.

Commercially available fumaryl chloride and two equivalents of(−)-menthol (both Sigma-Aldrich) are reacted to yielddi-(−)-menthylfumarate (7). A Diels-Alder reaction between (6) and (7)produces (8). Any E-isomer of the diene (<5%) that is present does notreact in the Diels-Alder reaction. Deprotection and epimerization of (8)in acid gives (3). The desilylation of (8) initially gave a mixture of2,3-cis- and 2,3-trans-ketones, which, driven by crystallization ofdesired (9), isomerized to the predominantly trans compound. Reductionof (9) with lithium tri-t-butoxy aluminum hydride (Li(t-BuO)₃AlH),followed by lithium aluminum hydride (LiAlH₄), produces triol (10),which is then protected with n-propyl sulfonyl chloride (nPrSO₂Cl₂) togive (11).

S-BTBA ((S)-1-[3,5-bis(trifluoromethyl)] phenylethanol)) (12) is reactedwith trichloroacetonitrile (Sigma-Aldrich) in the presence of base1,8-diazabicycloundec-7-ene (DBU) to produce imidate (13). HBF₄ is usedto catalyze the reaction of (11) with (13) to yield ether (14).Treatment with allylamine and bis-propylsulfonate cyclizes (14) toallylamine-protected pyrrolidine (15). Removal of the allyl protectinggroup with thiosalicylic acid and 1,4-bis(diphenylphosphino)butane(dppb), followed by bis(dibenzylideneacetone)palladium (Pd₂(dba)₃) andisolation with acetic acid gives crystalline (16). Finally, (16) isreacted with 1,3-cyclopentanedione (Sigma-Aldrich) in isopropyl alcoholto give Compound 1. Compound 1 is a white to off-white powder. It isfreely soluble in methanol, soluble in ethanol, slightly soluble inisopropyl acetate, sparingly soluble in isopropyl alcohol, ethylacetate, and acetonitrile, and insoluble in water.

Pharmaceutical Compositions

Compositions containing serlopitant or a pharmaceutically acceptablesalt, solvate or polymorph thereof as the active ingredient may beadvantageously used to treat chronic pruritus. While it is possible forserlopitant or a pharmaceutically acceptable salt, solvate or polymorphthereof to be administered alone, it is preferable to present it as aformulation. The compositions, or dosage forms, may be administered orapplied singly, or in combination with other agents. The formulationsmay also deliver serlopitant to a patient in combination with anotherpharmaceutically active agent.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional pharmaceutically acceptable carriercomprising inert ingredients, as well as any product which results,directly or indirectly, from combination, complexation or aggregation ofany two or more of the ingredients, or from dissociation of one or moreof the ingredients, or from other types of reactions or interactions ofone or more of the ingredients. In general, pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier. Said compositions are preparedaccording to conventional mixing, granulating, or coating methods,respectively, and contain about 0.1 to 75%, preferably about 1 to 50%,of the active ingredient.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. Pharmaceuticalcompositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, cornstarch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. A tablet may be made by compressing or molding the activeingredient optionally with one or more pharmaceutically acceptableingredients. Compressed tablets may be prepared by compressing, in asuitable machine, the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with a binder, lubricant, inertdiluent, surface active, or dispensing agent. Molded tablets may be madeby molding, in a suitable machine, a mixture of the powdered activeingredient and a suitable carrier moistened with an inert liquiddiluent.

Compositions for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil. Inparticular, a pharmaceutical composition of the present invention maycomprise a liquid-filled capsule dosage form in which the activeingredient is in solution in certain combinations of liquid andsemi-solid excipients. In one embodiment, the invention is directed to asolution comprising the active agent3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one(Compound 1) or a pharmaceutically acceptable salt, solvate or polymorphthereof, and an amphiphilic agent, said amphiphilic agent being a fattyacid ester of glycerol, propylene glycol or sorbitol, as described inU.S. Published Application No. 2010/0209496 (Dakou et al.), which isherein incorporated by reference in its entirety. Preferably, theamphiphilic agent consists essentially of mono- and di-glycerides of C8to C12 saturated fatty acids and mixtures thereof.

Compositions for oral administration may also be formulated as aqueoussuspensions containing the active ingredient in admixture withexcipients suitable for the manufacture of aqueous suspensions. Oilysuspensions may be formulated by suspending the active ingredient in asuitable oil. Oil-in-water emulsions may also be employed. Dispersiblepowders and granules suitable for preparation of an aqueous suspensionby the addition of water provide the active ingredient in admixture witha dispersing or wetting agent, suspending agent and one or morepreservatives.

The active ingredient of the present invention may be administered in anoral sustained release formulation. “Sustained release” refers torelease of an active agent from a dosage form at a rate effective toachieve a therapeutic amount of the agent, or active metabolite thereof,in the systemic blood circulation over a prolonged period of timerelative to that achieved by oral administration of a conventionalformulation of the agent. Release of the agent occurs over an extendedperiod of hours, for example, over a period of at least 6 hours, over aperiod of at least 8 hours, over a period of at least 12 hours, or overa period of at least 24 hours.

Suitable topical formulations and dosage forms include ointments,creams, gels, lotions, pastes, and the like, as described in Remington:The Science and Practice of Pharmacy (21^(st) Edition, University of theSciences in Philadelphia, 2005). Ointments are semi-solid preparationsthat are typically based on petrolatum or other petroleum derivatives.The specific ointment base to be used, as will be appreciated by thoseskilled in the art, is one that will provide for optimum drug delivery,and, preferably, will provide for other desired characteristics as well,e.g., emolliency or the like. Creams are viscous liquids or semisolidemulsions, either oil-in-water or water-in-oil. Cream bases arewater-washable, and contain an oil phase, an emulsifier and an aqueousphase. The oil phase, also called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. The aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. Gels are semisolid, suspension-typesystems. Single-phase gels contain organic macromolecules (polymers)distributed substantially uniformly throughout the carrier liquid, whichis typically aqueous, but also, preferably, contain an alcohol such asethanol or isopropanol and, optionally, an oil. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixingor stirring, or combinations thereof. Lotions are preparations to beapplied to the skin surface without friction, and are typically liquidor semiliquid preparations in which solid particles, including theactive agent, are present in a water or alcohol base. Lotions areusually suspensions of finely divided solids and will typically containsuspending agents to produce better dispersions as well as compoundsuseful for localizing and holding the active agent in contact with theskin. Pastes are semisolid dosage forms in which the active agent issuspended in a suitable base. Depending on the nature of the base,pastes are divided between fatty pastes or those made from single-phaseaqueous gels.

Various additives, known to those skilled in the art, may be included inthe topical formulations. For example, solvents, including relativelysmall amounts of alcohol, may be used to solubilize certain drugsubstances. Other optional additives include opacifiers, antioxidants,fragrance, colorant, gelling agents, thickening agents, stabilizers,surfactants and the like. Other agents may also be added, such asantimicrobial agents, to prevent spoilage upon storage, i.e., to inhibitgrowth of microbes such as yeasts and molds. For those drugs having anunusually low rate of permeation through the skin or mucosal tissue, itmay be desirable to include a permeation enhancer in the formulation.The formulation may also contain irritation-mitigating additives tominimize or eliminate the possibilty of skin irritation or skin damageresulting from the drug, the enhancer, or other components of the dosageform. The formulations may also contain ether physiologically acceptableexcipients or other minor additives, such as fragrances, dyes,emulsifiers, buffers, cooling agents (e.g. menthol), antibiotics,stabilizers or the like. In some instances, one component may serve morethan one function.

The concentration of the active agent in a topical formulation can varya great deal, and will depend on a variety of factors, including thedisease or condition to be treated, the nature and activity of theactive agent, the desired effect, possible adverse reactions, theability and speed of the active agent to reach its intended target, andother factors within the particular knowledge of the patient andphysician. The formulations will typically contain on the order of about0.1 wt % to 50 wt % active agent, preferably about 0.1 wt % to 5 wt %active agent, optimally about 5 wt % to 20 wt % active agent.

In some embodiments, a topical dosage form of serlopitant is formulatedas a buccal or sublingual tablet or pill. Advantages of a buccal orsublingual tablet or pill include avoidance of first-pass metabolism andcircumvention of gastrointestinal absorption. In addition to atherapeutically effective amount of serlopitant, the buccal orsublingual tablet or pill can contain suitable excipients, includingwithout limitation any combination of fillers and diluents (e.g.,mannitol and sorbitol), binding agents (e.g., sodium carbonate), wettingagents (e.g., sodium carbonate), disintegrants (e.g., crospovidone andcroscarmellose sodium), lubricants (e.g., silicon dioxide [includingcolloidal silicon dioxide] and sodium stearyl fumarate), stabilizers(e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor),sweetening agents (e.g., sucralose), and coloring agents (e.g., yellowiron oxide). The buccal or sublingual tablet or pill containingserlopitant can be used to treat, e.g., any pruritus-associatedcondition described herein.

The pharmaceutical compositions of the present invention may beformulated as a depot formulation for administration via intramuscularor subcutaneous injection. Depot formulations are efficient,well-tolerated, sustained or delayed release compositions of the activeingredient that are therapeutically effective for a number of weeks,such as at least one week, at least two weeks, at least three weeks, atleast four weeks, at least five weeks, or at least six weeks or more. Inaddition to the active agent, additional ingredients may be used in thedepot formulations of the present invention including surfactants,solubilizers, emulsifiers, preservatives, isotonicity agents, dispersingagents, wetting agents, fillers, solvents, buffers, stabilizers,lubricants, and thickening agents. A combination of additionalingredients may also be used. The amount of the active ingredient in adepot formulation will depend upon the severity of the pruritus beingtreated.

The compositions of the present invention may be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. The term “unit dosage form” is taken to mean a singledose wherein all active and inactive ingredients are combined in asuitable system, such that the patient or person administering the drugto the patient can open a single container or package with the entiredose contained therein, and does not have to mix any components togetherfrom two or more containers or packages. Typical examples of unit dosageforms are tablets or capsules for oral administration. These examples ofunit dosage forms is not intended to be limiting in any way, but merelyto represent typical examples in the pharmacy arts of unit dosage forms.

The compositions of the present invention may also be presented as akit, whereby two or more components, which may be active or inactiveingredients, carriers, diluents, and the like, are provided withinstructions for preparation of the actual dosage form by the patient orperson administering the drug to the patient. Such kits may be providedwith all necessary materials and ingredients contained therein, or theymay contain instructions for using or making materials or componentsthat must be obtained independently by the patient or personadministering the drug to the patient.

Topical Compositions Comprising Serlopitant

Topical formulations for application to the skin or mucosa can be usefulfor treatment of conditions of the upper skin or mucosal layers and fortransdermal or transmucosal administration of an active agent to thelocal tissue underlying the skin or mucosa and, if desired, into theblood for systemic distribution. Advantages of topical administrationcan include avoidance of first-pass metabolism, circumvention ofgastrointestinal absorption, delivery of an active agent with arelatively short biological half-life, more controlled release of theactive agent, administration of a more uniform plasma dosing of theactive agent, and improvement in user compliance.

In general and in addition to the disclosure on topical formulationsdescribed elsewhere herein, compositions suitable for topicaladministration include without limitation liquid or semi-liquidpreparations such as sprays, gels, liniments, lotions, oil-in-water orwater-in-oil emulsions such as creams, foams, ointments and pastes, andsolutions or suspensions such as drops (e.g., eye drops, nose drops andear drops). In some embodiments, a topical composition comprises anactive agent dissolved, dispersed or suspended in a carrier. The carriercan be in the form of, e.g., a solution, a suspension, an emulsion, anointment or a gel base, and can contain, e.g., petrolatum, lanolin, awax (e.g., bee wax), mineral oil, a long-chain alcohol, polyethyleneglycol or polypropylene glycol, a diluent (e.g., water and/or an alcohol[e.g., ethanol or propylene glycol], an emulsifier, a stabilizer or athickening agent, or a combination thereof. A topical composition caninclude, or a topical formulation can be administered by means of, e.g.,a transdermal patch, a microneedle patch or an iontophoresis device. Atransdermal patch can contain. e.g., a microporous membrane made of asuitable material (e.g., cellulose nitrate or acetate, propylene or apolycarbonate), a skin adhesive and backing material. A topicalcomposition can deliver the active agent transdermally (includingpercutaneously and transmucosally) via a concentration gradient or anactive mechanism (e.g., ionospheres).

Representative kinds of topical compositions are described below forpurposes of illustration.

I. Topical Compositions Comprising a Permeation Enhancer

In some embodiments, a topical composition comprises serlopitant and apermeation enhancer. The composition can optionally contain anadditional therapeutic agent. In certain embodiments, the compositioncontains serlopitant in free base form.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). In certain embodiments, the permeationenhancer is N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate,isopropyl myristate, oleic acid, glyceryl oleate or sodium laurylsulfoacetate, or a combination thereof. In certain embodiments, thecomposition contains on a weight/volume (w/v) basis the permeationenhancer in an amount of about 1-20%, 1-15%, 1-10% or 1-5%. To enhancefurther the ability of the therapeutic agent(s) to penetrate the skin ormucosa, the composition can also contain a surfactant, an azone-likecompound, an alcohol, a fatty acid or ester, or an aliphatic thiol.

The composition can further contain one or more additional excipients.Suitable excipients include without limitation solubilizers (e.g., C₂-C₈alcohols), moisturizers or humectants (e.g., glycerol [glycerin],propylene glycol, amino acids and derivatives thereof, polyamino acidsand derivatives thereof, and pyrrolidone carboxylic acids and salts andderivatives thereof), surfactants (e.g., sodium laureth sulfate andsorbitan monolaurate), emulsifiers (e.g., cetyl alcohol and stearylalcohol), thickeners (e.g., methyl cellulose, ethyl cellulose,hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrolidone,polyvinyl alcohol and acrylic polymers), and formulation bases orcarriers (e.g., polyethylene glycol as an ointment base). As anon-limiting example, the base or carrier of the composition can containethanol, propylene glycol and polyethylene glycol (e.g., PEG 300), andoptionally an aqueous liquid (e.g., isotonic phosphate-buffered saline).

The topical composition can have any suitable dosage form, such as asolution (e.g., eye drop, nose drop or ear drop), a suspension, anemulsion, a cream, a lotion, a gel, an ointment, a paste, a jelly, afoam, a shampoo, or a spray. In some embodiments, the composition isapplied to the skin or mucosa covering a surface area of about 10-800cm², 10-400 cm² or 10-200 cm². The composition can deliver thetherapeutic agent(s) to the skin or mucosa or the underlying tissue. Thecomposition can also be formulated for transdermal administration of thetherapeutic agent(s) to the systemic circulation, e.g., as a transdermalpatch or a microneedle patch.

II. Topical Composition Comprising a Permeation Enhancer and a VolatileLiquid

In further embodiments, a topical composition comprises serlopitant, apermeation enhancer and a volatile liquid. The composition canoptionally contain an additional therapeutic agent. In certainembodiments, the composition contains serlopitant in free base form.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). In some embodiments, the permeationenhancer is selected from the group consisting of C₈-C₁₈ alkylaminobenzoates (e.g., C₈-C₁₈ alkyl p-aminobenzoates), C₈-C₁₈ alkyldimethylaminobenzoates (e.g., C₈-C₁₈ alkyl p-dimethylaminobenzoates),C₈-C₁₈ alkyl cinnamates, C₈-C₁₈ alkyl methoxycinnamates (e.g., C₈-C₁₈alkyl p-methoxycinnamates), and C₈-C₁₈ alkyl salicylates. In certainembodiments, the permeation enhancer is octyl salicylate, octylp-dimethylaminobenzoate or octyl p-methoxycinnamate, or a combinationthereof.

The volatile liquid can be any volatile, skin- or mucosa-tolerantsolvent in certain embodiments, the volatile liquid is a C₂-C₅ alcoholor an aqueous solution thereof, such as ethanol or isopropanol or anaqueous solution thereof. An aerosol propellant (e.g., dimethyl ether)can be considered as a volatile liquid. In some embodiments, thevolatile liquid functions as a carrier or vehicle of the composition.

The composition can optionally contain a thickening agent. Non-limitingexamples of thickening agents include cellulosic thickening agents(e.g., ethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethylcellulose), povidone, polyacrylic acids/polyacrylates (e.g.,Carbopol® polymers), Sepigel® (polyacrylamide/isoparaffin/laureth-7),and the Gantrez® series of polymethyl vinyl ether/maleic anhydridecopolymers (e.g., butyl ester of PMV/MA copolymer Gantrez® A-425).

In some embodiments, the composition contains on a weight basis about0.5-10%, 0.5-5% or 1-5% of serlopitant, about 1-20%, 1-15% or 1-10% ofthe permeation enhancer, and about 40-98%, 45-95%, 50-90% or 60-80% ofthe volatile liquid. In further embodiments, the composition optionallycontains on a weight basis about 1-40%, 1-30%, 1-20% or 5-20% waterand/or about 0.1-15%, 0.5-10% or 1-5% of a thickening agent.

For purposes of illustration, in certain embodiments a topical spraycomposition contains about 0.5-5% w/v of serlopitant, about 2-10% w/v ofoctyl salicylate or octyl p-methyoxycinnamate, and about 96% aqueousethanol as the carrier. In further embodiments, a topic gel compositioncomprises about 0.5-5% w/v of serlopitant, about 1-10% w/v of octylsalicylate or octyl p-methyoxycinnamate, about 0.5-5% w/v of a Carbopol®polyacrylic acid, and about 70% aqueous ethanol as the carrier, andoptionally about 1-10% w/v of a basic solution (e.g., 0.1 N NaOH). Inadditional embodiments, a topical lotion composition contains about0.5-5% w/v of serlopitant, about 1-10% w/v of octyl salicylate or octylp-methyoxycinnamate, about 1-5% w/v of ethyl cellulose or hydroxypropylcellulose, and about 90% aqueous ethanol as the carrier.

The composition can further comprise other excipients, such as acompounding agent (e.g., paraffin oil, silicone oil, a vegetable oil, ora fatty ester such as isopropyl myristate), a diluent, a co-solvent(e.g., acetone or a glycol ether such as diethylene glycol monoethylether), an emulsifier, a surfactant (e.g., an ethoxylated fatty alcohol,glycerol mono stearate or a phosphate ester), a stabiliser, anantioxidant or a preservative (e.g., a hydroxybenzoate ester), or acombination thereof. For example, a co-solvent and/or a surfactant canbe used to maintain the therapeutic agent(s) in solution or suspensionat the desired concentration.

The topical composition can have any suitable dosage form, such as acream, a lotion, a gel, an ointment, a mousse, a spray or aerosol, orany transdermal device (e.g., a patch) that administers a drug byabsorption through the skin or mucosa. In some embodiments, the topicalcomposition is applied to the skin or mucosa covering a surface area ofabout 10-800 cm², 10-400 cm² or 10-200 cm².

III. Topical Compositions Comprising a Permeation Enhancer and AnotherExcipient

In yet further embodiments, a topical composition comprises serlopitant,a permeation enhancer, and at least one of a lipophilic solvent, aformulation base and a thickener. In some embodiments, the compositioncontains a lipophilic solvent and a formulation base, or the samesubstance can function as both a lipophilic solvent and a formulationbase. In further embodiments, the composition contains a lipophilicsolvent, a formulation base and a thickener. The composition canoptionally comprise an additional therapeutic agent. In certainembodiments, the composition contains serlopitant in free base form.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). Non-limiting examples of permeationenhancers include dimethyl sulfoxide (DMSO), decylmethylsulfoxide,laurocapram, pyrrolidones (e.g., 2-pyrrolidone andN-methyl-2-pyrrolidine), surfactants, alcohols (e.g., oleyl alcohol),polyethylene glycol (e.g., PEG 400), diethylene glycol monoethyl other,oleic acid, and fatty acid esters (e.g., isopropyl myristate, methyllaurate, glycerol monooleate, and propylene glycol monooleate).

Non-limiting examples of lipophilic solvents include lipophilic alcohols(e.g., hexylene glycol, octyldodecanol, oleyl alcohol and stearylalcohol), polyethylene glycol (e.g., PEG 100, PEG 300, PEG 400 and PEG3350), diethylene glycol monoethyl ether, polysorbates (e.g., Tween® 20to 80), Labrasol, fatty acid esters (e.g., isopropyl myristate anddiisopropyl adipate), diethyl sebacate, propylene glycol monocaprylate,propylene glycol laurate, mono- and di-glycerides (e.g., Capmul® MCM),medium-chain triglycerides, caprylic/capric triglyceride, glycerylmonocaprylate, glyceryl mono-oleate, glyceryl mono-linoleate, glycerololeate/propylene glycol, mineral oil, and vegetable oils.

A lipophilic solvent may also function as a formulation base or carrier.For example, polyethylene glycol (e.g., from PEG 100 to PEG 3500, suchas PEG 300, PEG 400 and PEG 3350) can function as a lipophilic solventand a formulation base.

The composition can also contain a hydrophilic solvent, such as a C₁-C₅alcohol (e.g., ethanol, isopropanol, glycerol, propylene glycol and1,2-pentanediol) and/or water.

The composition can contain a thickener to increase the viscosity and/orthe physical stability of the composition. Examples of thickenersinclude without limitation glycerol, stearyl alcohol, and polymers(e.g., polydimethylsiloxane [dimethicone] and Carbopol® polymers).

In some embodiments, the composition further contains an antioxidant.Non-limiting examples of antioxidants include butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), tocopherols (e.g., Vitamin E andesters thereof), flavinoids, glutathione, ascorbic acid and estersthereof, DMSO, and chelating agents (e.g., EDTA and citric acid).

In certain embodiments, the topical composition comprises on a w/w basisabout 0.5-10% or 1-5% of serlopitant, about 2-30% or 5-20% of apermeation enhancer, about 20-80% or 30-70% of a lipophilic solvent thatmay also function as a formulation base, about 0.1-10% or 1-7.5% of athickener, and about 0.01-2% or 0.05-1% of an antioxidant. As anon-limiting example, a topical composition can contain serlopitant, PEG400 and/or PEG 3350 as lipophilic solvent(s) and formulation base(s),diethylene glycol monoethyl ether, oleyl alcohol and/or isopropylmyristate as permeation enhancer(s), stearyl alcohol as a thickener, andBHT as an antioxidant.

The topical composition can have any suitable dosage form, such a ascream, a lotion, a gel, an ointment, a jelly, a paste, or anytransdermal device (e.g., a patch) that administers a drug by absorptionthrough the skin or mucosa.

IV. Topical Compositions Comprising a Permeation Enhancer and anAdhesive

In additional embodiments, a topical composition comprises serlopitant,a permeation enhancer and an adhesive. The composition can optionallycontain an additional therapeutic agent. In certain embodiments, thecomposition contains serlopitant in free base form.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). The permeation enhancer can be, e.g., afatty acid ester having a fatty acyl chain length of C₈-C₂₀ or C₁₂-C₁₈and a C₁-C₅ or C₂-C₄ alcohol component (e.g., isopropanol). In certainembodiments, the permeation enhancer is isopropyl myristate or isopropylpalmitate. In some embodiments, the permeation enhancer is in an amountof about 0.1-20%, 0.5-15%, 1-15%, 2-12% or 4-10% by weight of thecomposition or the skin-contacting layer of a transdermal patch.

The adhesive maintains contact of the topical composition to the skin ormucosa. Non-limiting examples of adhesives include acrylic/acrylates(e.g., polyacrylates, including polyalkyl acrylates and Duro-Tak®polyacrylates), polyvinyl acetate, ethylenevinylacetate copolymers,polysiloxanes, polyurethanes, plasticized polyether block amidecopolymers, natural and synthetic rubbers, plasticized styrene-butadienerubber block copolymers (e.g., Duro-Tak® 87-6173), and mixtures thereof.

The topical composition can comprise one or more additional excipients.The additional excipient(s) can be, e.g., a diluent, an emollient, aplasticizer, or an agent that reduces irritation to the skin or mucosa,or a combination thereof.

In certain embodiments, the topical composition prior to application tothe skin or mucosa is substantially free of water, tetraglycol(glycofurol) and/or a hydrophilic organic solvent (e.g., a C₁-C₅alcohol).

The composition can administer the therapeutic agent(s) transdermally(including percutaneously and transmucosally) through a body surface ormembrane such as intact unbroken skin or intact unbroken mucosal tissueinto the systemic circulation.

In some embodiments, the topical composition is in the form of atransdermal patch for application to the skin or mucosa. The patch has askin- or mucosa-contacting layer (“skin-contacting layer” forsimplicity) laminated or otherwise attached to a support layer. Theskin-contacting layer can be covered by a removable release liner beforeuse to protect the skin-contacting surface and to keep it clean until itis applied to the skin or mucosa.

The support layer of the patch acts as a support for the skin-contactinglayer and as a barrier that prevents loss of the therapeutic agent(s) inthe skin-contacting layer to the environment. The material of thesupport layer is compatible with the therapeutic agent(s), thepermeation enhancer and the adhesive, and is minimally permeable to thecomponents of the patch. The support layer can be opaque to protect thecomponents of the patch from degradation via exposure to ultravioletlight. The support layer is also capable of binding to and supportingthe adhesive layer, yet is sufficiently pliable to accommodate themovements of the subject using the patch. The material of the supportlayer can be, e.g., a metal foil, a metalized polyfoil, or a compositefoil or film containing a polymer (e.g., a polyester [such as polyesterterephthalate] or aluminized polyester, polyethylene, polypropylene,polytetrafluoroethylene, a polyethylene methyl methacrylate blockcopolymer, a polyether block amide copolymer, a polyurethane,polyvinylidene chloride, nylon, a silicone elastomer, rubber-basedpolyisobutylene, styrene, or a styrene-butadiene or styrene-isoprenecopolymer). The release liner can be made of the same material as thesupport layer, or can be a film coated with an appropriate releasesurface.

Pruritus

Pruritus is a physiological perception within the sensory neuronalnetwork in the skin which, along with pain and physical or mechanicalstimuli, can serve as a warning system against potential bodily threats.Itching is an unpleasant sensation that can lead to scratching, but isindependent of pain. The International Federation for the Study of Itch(IFSI) defines chronic pruritus (as opposed to acute pruritus) asitching that lasting six weeks or longer (S. Ständer et al., Acta Derm.Venereol., 2007, 87(4):291-4). Several factors in and on the skin canactivate the sensory nerve fibers or modulate their activity and thustrigger, suppress, or exacerbate itching. Physical stimuli such as coldand heat modulate the perception of itching; painful heat and cold cansignificantly diminish it, while moderate cold intensifies it (Valet etal., J. Invest. Dermatol., 2006, 128(2):426-33.). Mechanical factorssuch as rubbing or scratching the skin can briefly suppress itching byactivating nerve fibers that selectively activate and de-activatecertain areas of the brain (Yosipovitch et al., J. Invest. Dermatol.,2008, 128(7):1806-11).

Chronic pruritus can seriously diminish the quality of life in itssufferers as it can be intractable and incapacitating. It is a seriouslydebilitating condition, comparable to chronic pain, which can lead tofrustration, desperation and depression. Moreover, chronic scratchingoften produces open skin lesions, subject to primary or secondaryinfection, scarring and potential disfigurement. Chronic pruritus isoften an indication of underlying disease and is always present indiseases such as urticaria and atopic dermatitis. Diagnosis of theunderlying disease is desirable and clinical presentation, patienthistory, and patient self-evaluation form important parts of suchdiagnosis.

According to Arbeitsgemeinschaft der Wissenschaftlichen MedizinischenFachgesellschaften (AWMF) (Association of the Scientific MedicalSocieties of Germany) guidelines, diseases and disorders with chronicpruritus as a symptom may be classified by whether the skin is inflamedor not inflamed (S. Ständer, Clin. Exp. Dermatol., 2006, 31(6):762-7).The IFSI further characterizes pruritus as dermatologic, systemic,neurogenic, psychogenic, mixed and other. Chronic pruritus onnon-inflamed skin may result from dermatological diseases, includingatopic diathesis, asteatosis, porphyria, suburticarial stages of solarinjury, cholinergic, adrenergic urticaria, initial stage ofmastocytosis, bullous pemphigoid, and Duhring's disease (dermatitisherpetiformis); from endocrine and metabolic disorders, such as chronicrenal insufficiency and the dialysis needed treat it, hepatopathies withcholestasis, diabetes mellitus, malabsorption disorders, anorexia,gluten-enteropathies, hyperthyroidism, hypothyroidism,hyperparathyroidism, and perimenopausal pruritus; from infectionsincluding HIV infection, parasites, Helicobacter pylori, andhelminth-related; from hemotological and lymphoproliferative diseasessuch as iron deficiency, polycythaemica vera, hypereosinophiliasyndrome, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin'slymphoma, plasmocytoma, and systemic mastocytosis; from solid malignanttumors including cervical, breast, prostate or large intestinal cancer,and carcinoid tumors; from neurological disorders such as brachioradialpruritus, notalgia paraesthetica, post-zoster neuralgia, vulvodynia,neuropathies of various origin, multiple sclerosis, tumors, abscesses,underperfusion, infarctions involving the CNS/spinal cord; frompsychogenic disorders such as depression, schizophrenia, and tactilehallucinations; and from intrahepatic cholestasis in pregnant women(pruritus gravidarum).

Chronic pruritus on inflamed skin may be observed in patients withinflammatory skin disease including, but not limited to, atopicdermatitis, allergic, irritant contact dermatitis, exsiccationdermatitis, nummular and dyshidrotic dermatitis, lichen planus, lichensclerosus et atrophicus, polymorphous light eruption psoriasis, Grover'sdisease, mucinosis, mastocytosis, and urticaria; infectious skindiseases such as mycoses, bacterial and viral infections, scabies,pediculosis, insect bites, and folliculitides; autoimmune skin diseasesincluding Bullous skin disorders, especially dermatitis herpetiformis(Duhring's disease), and bullous pemphigoid; genodermatoses such asDarer's disease, and Hailey-Hailey disease; pregnancy-related skindiseases including polymorphic eruption of pregnancy (PEP, formerlyknown as PUPPP), atopic eruption of pregnancy, and pemphigoidgestationis; and neoplasias such as cutaneous T-cell lymphoma(especially the erythrodermic form).

Prurigo nodularis (PN), or nodular prurigo, is a particularly severeform of chronic itching that may treated by methods and compositions ofthe present invention. Characterized by itchy, excoriated, lichenifiedpapules and nodules. PN can occur at any age, but most often presents inmiddle-aged and elderly patients on their arms and legs (E. Weisshaarand S. Ständer, Acta Derm. Venereol., 2012, 92:532-533). The etiology ofPN is unknown, but it usually occurs in patients with a personal orfamily history of atopic dermatitis, and often with concomitant medicalconditions such as hepatic or renal function, local trauma or insult tothe skin, infection, and HIV or other immunodeficiencies. PN may resultin permanent changes to the skin, including nodular lichenification,hyperkeratosis, hyperpigmentation, and skin thickening.

Combination Therapies with Serlopitant and Other Antipruritic Agents

Serlopitant, alone or in combination with one or more additionalantipruritic agents, can be used to treat pruritus (including acute andchronic pruritus) associated with any condition. The itch sensation canoriginate, e.g., in the peripheral nervous system (e.g., dermal orneuropathic itch) or in the central nervous system (e.g., neuropathic,neurogenic or psychogenic itch).

Examples of pruritus-associated conditions include without limitationthose described elsewhere herein and the following:

dermatological disorders and conditions (including inflammatory andnon-inflammatory skin conditions), including but not limited to adultblaschkitis, amyloidoses (e.g., primary cutaneous amyloidosis [includingmacular amyloidosis, lichen amyloidosis and nodular amyloidosis]), burns(e.g., chemical burns and sunburn), dermatitis (e.g., atopic dermatitis,contact dermatitis (including allergic contact dermatitis, irritantcontact dermatitis and photodermatitis), eczema (e.g., autosensitizationdermatitis, dermatitis herpetiformis [Duhring's disease], discoideczema, dyshidrosis [pompholyx], hand eczema, id reaction [generalizedeczema], nummular eczema, stasis dermatitis [gravitational eczema],venous eczema and xerotic eczema), pustular dermatitis (e.g.,eosinophilic pustular folliculitis [Ofuji's disease], reactive arthritis[Reiter's disease] and subcorneal pustular dermatosis [Sneddon-Wilkinsondisease]), and seborrheic dermatitis (e.g., infantile seborrheicdermatitis, Leiner's disease and pityriasis simplex capillitii[dandruff])}, erythroderma (exfoliative dermatitis), follicutis,pseudofolliculitis barbae (barber's itch), hidradenitis suppurativa,ichthyoses (e.g., ichthyosis vulgaris, congenital ichthyosis,epidermolytic hyperkeratosis and lamellar ichthyosis), lichen planus(e.g., cutaneous lichen planus and oral lichen planus), lichen sclerosis(e.g., lichen sclerosis et atrophicus of the vulva), lichen simplex(e.g., lichen simplex chronicus [neurodermatitis]), linear IgA bullousdermatosis (linear IgA dermatosis), lupus erythematosus (e.g., cutaneouslupus erythematosus, discoid lupus erythematosus and systemic lupuserythematosus), miliaria (sweat rash), palmoplantar keratoderma (e.g.,punctate palmoplantar keratoderma), pityriasis (e.g., pityriasisamiantacea, pityriasis lichenoides [including pityriasis lichenoideschronica and pityriasis lichenoides at varioliformis acuta], pityriasisrosea, pityriasis rubra pilaris [Devergie's disease] and pityriasisversicolor), prurigo (e.g., actinic prurigo, Besnier's prurigo, prurigonodularis, prurigo pigmentosa and prurigo simplex), pruritus ani,pruritus scroti, pruritus vulvae, psoriasis (e.g., erythrodermicpsoriasis, Guttate psoriasis [eruptive psoriasis], psoriasis vulgaris[chronic stationary psoriasis], pustular psoriasis, and pustulosispalmaris plantaris), parapsoriasis (e.g., large plaque parapsoriasis andsmall plaque parapsoriasis [chronic superficial dermatitis]), punctapruritica (itchy points), rashes (e.g., intertrigo and perioraldermatitis), rosacea, urticaria (e.g., contact urticaria [includinghives] and idiopathic urticaria), vitiligo, xerosis (dry skin), chappedskin (e.g., chapped feet), scalp pruritus, scab healing, scardevelopment, and development of moles, pimples and ingrown hair;

medical disorders and conditions (including peripheral and systemicdisorders), including but not limited to atopic diathesis, autoimmunedisorders (e.g., celiac disease, dermatomyositis, Graves' disease,pemphigoid [e.g., bullous pemphigoid], scleroderma and Sj□gren'ssyndrome), blood disorders (e.g., anemia [e.g., iron deficiency anemiaand sickle cell anemia], hypercalcemia, myelodysplastic syndromes andpolycythemia [e.g., polycythemia vera]), Creutzfeldt-Jakob disease(e.g., prion pruritus), diabetes mellitus, genetic diseases (e.g.,Alagille syndrome, Darer's disease, epidermolysis bullosa, Hailey-Haileydisease and Sj□gren-Larsson syndrome), Grover's disease, HIV/AIDS,kidney disorders (e.g., diabetic nephropathy, glomerulonephritis,chronic kidney disease, end-stage kidney disease and chronic kidneyfailure), uraemia (e.g., uremic pruritus [renal pruritus]), ver diseases(e.g., cirrhosis [e.g., primary biliary cirrhosis], hepatitis [includinghepatitis A, B, C, D and E and their chronic conditions], and liverfailure), cholestasis (e.g., cholestatic pruritus), jaundice (e.g.,biliary pruritus), lymphadenopathy (e.g., enlarged lymph nodes), mastcell diseases (e.g., mast cell activation syndrome and mastocytosis),multiple sclerosis, neuropathies (e.g., peripheral neuropathy [e.g.,brachioradial pruritus, notalgia paresthetica, polyneuropathy and smallfiber peripheral neuropathy]), nerve irritation, pinched nerves,parathyroid disorders (e.g., hyperparathyroidism andhypoparathyroidism), thyroid disorders (e.g., hyperthyroidism,hypothyroidism and myxedema), stroke, cancers (e.g., carcinoid syndrome,leukemia (e.g., leukemia cutis and lymphatic leukemia), lymphomas (e.g.,Hodgkin's disease and non-Hodgkin lymphomas [e.g., cutaneous B-celllymphoma and cutaneous T-cell lymphoma (including mycosis fungoides andSézary's disease)]), Kaposi's sarcoma, multiple myeloma and skincancers), tumors (e.g., brain tumor, plasmacytoma, and solid tumors ofthe cervix, colon and prostate), paraneoplastic pruritus, psychiatricdisorders (e.g., stress, anxiety disorders, delusional parasitosis,depression, obsessive-compulsive disorders [e.g., neurotic excoriation],and tactile hallucinations), aging (e.g., senile pruritus) and changesin hormonal balances associated with aging (e.g., perimenopause andmenopause);

infections and infestations, including but not limited to cercarialdermatitis (swimmer's itch), insect bites and stings (e.g., by ants,bees, chiggers, fleas, lice [including body lice, head lice and pubiclice], mites, mosquitos, spiders, ticks and wasps), scabies, bacterialinfections (e.g., abscess dermatitis gangrenosa, ecthyma, erythrasma,impetigo and Lyme disease), fungal infections (e.g., candidiasis,dermatophytosis, tines corporis [ringworm of the body], tines cruris[jock itch] and tines pedis [athlete's foot]), viral infections (e.g.,herpes (including herpes zoster [shingles] and post-herpetic itch),measles, parvovirus infections (e.g., parvovirus B19), varicella(chickenpox) and Yellow fever), and worm infections (e.g., helminths(e.g., helminthiasis [helminthosis]), hookworms (e.g., cutaneous larvamigrans), Onchocerca worms (e.g., onchocerciasis [river blindness]),pinworms, roundworms (e.g., filarasis and trichinosis) and Schistosomaworms (e.g., schistosomiasis));

reactions to allergens and irritants, including but not limited toallergic rhinitis (e.g., pollinosis [including hay fever]), asthma,animal allergens (e.g., cat dander and dog dander), chemical allergens(e.g., acids [e.g., abietic acid and sorbic acid], cosmetics,detergents, dyes, fabric softeners, fungicides, hydroxyethyl starch andlatex), food allergens (e.g., milk proteins, peanuts, tree nuts,seafood, spices, preservatives [e.g., nitrates], vitamins [e.g.,vitamins A and B], alcohol, caffeine and monosodium glutamate), metaland metal salt allergens (e.g., chromium, cobalt, gold and nickel andsalts thereof), plant allergens (e.g., Balsam of Peru and urushiol[e.g., in poison ivy, poison oak and poison sumac]), chemical irritants(e.g., acids, alkalis, metalworking fluids, solvents, surfactants,detergents, soaps, cleaning products, cosmetics, perfumes, deodorants,antiperspirants, food flavorings, spices, preservatives [e.g.,formaldehyde and parabens], monomers and polymers [e.g., acrylics, epoxyresins, ethylene oxide, latex and lacquers], and oils [e.g., kerosene]),fabrics (e.g., wool), plant irritants (e.g., alkyl resorcinols [e.g., inGrevillea banksii, Grevillea “Robyn Gordon” and Gingko biloba]), andphysical irritants (e.g., water [e.g., aquadynia and aquagenicpruritus), low humidity from air conditioning, and cold temperature);

pruritus caused by drugs/medication, including but not limited tochloroquine, hydroxyethyl cellulose, hydroxyethyl starch,angiotensin-converting enzyme inhibitors, xanthine oxidase inhibitors(e.g., allopurinol), antibiotics (e.g., isoniazid, neomycin, penicillin,sulfonamides and vancomycin), antifungals (e.g., fluconazole,griseofulvin, itraconazole and ketoconazole),neuroleptics/antipsychotics (e.g., phenothiazines), antiarrhythmic drugs(e.g., amiodarone and quinidine), chemotherapeutic drugs, diuretic drugs(e.g., hydrochlorothiazide), statins (e.g., simvastatin), and drugs(e.g., opioids) that activate the histamine H₁ receptor or triggerhistamine release; and

conditions related to pregnancy, including but not limited togestational pemphigoid, impetigo herpetiformis, intrahepatic cholestasisof pregnancy (pruritus gravidarum), polymorphic eruption of pregnancy,prurigo of pregnancy, pruritic folliculitis of pregnancy, and pruriticurticarial papules and plaques of pregnancy.

One or more additional antipruritic agents can optionally be used incombination with serlopitant to treat pruritus (including acute andchronic pruritus). Examples of antipruritic agents include withoutlimitation:

antihistamines, including but not limited to antihistamines that inhibitaction at the histamine H, receptor (e.g., acrivastine, antazoline,azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine,carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine,chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine,dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene,diphenhydranine, doxepin, doxylamine, ebastine, embramine, fexofenadne,hydroxyzine, levocetirizine, loratadine, meclozine, mepyramine,mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine,phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine,tripelennamine and triprolidine), and antihistamines that inhibit actionat the histamine H₄ receptor (e.g., thioperamide, JNJ 7777120 andVUF-6002), and analogs and derivatives thereof;

serotonin receptor antagonists, including but not limited to 5-HT₂antagonists (e.g., clozapine, cyproheptadine, ketanserin, pizotifen andquetiapine) and 5-HT₃ antagonists (e.g., alosetron, cilansetron,dolasetron, granisetron, ondansetron, palonosetron and tropisetron), andanalogs and derivatives thereof;

neurokinin-1 (NK-1) receptor antagonists, including but not limited toaprepitant, casopitant (GW679769), dapitant, ezlopitant, fosaprepitant,lanepitant (LY-303870), maropitant, netupitant, nolpitant, orvepitant,rolapitant, vestipitant, vofopitant, AV-818, BIIF 1149CL, CP122,721,DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102 and TA-5538,and analogs and derivatives thereof;

opioid receptor antagonists, including but not limited to butorphanol,cyprodime, levallorphan (lorfan or naloxiphan), nalbuphine, nalorphine(lethidrone or nalline), naloxone, naloxol, nalmefene, naltrexone (e.g.,naltrexone 1% cream) and naltrexol, and analogs and derivatives thereof;

opioid receptor agonists, including but not limited to selective kappaopioid receptor agonists (e.g., asimadoline, bremazocine, dynorphin,enadoline, ketazocine, nalfurafine, salvinorin A, 2-methoxymethylsalvinorin B, 2-ethoxymethyl salvinorin B, 2-fluoroethoxymethylsalvinorin 8, spiradoline, tifluadom, BRL-52537, FE 200665, GR-9696,HZ-2, ICI-199,441, ICI-204,448, LPK-26, U-50488 and U-69,593), andanalogs and derivatives thereof;

Janus kinase (JAK) inhibitors, including but not limited to JAK1inhibitors (e.g., GLPG0634 and GSK2586184), JAK2 inhibitors (e.g.,lestaurtinib, pacritinib, CYT387 and TG101348), JAK1/JAK2 inhibitors(e.g., baridcitinib and ruxolitinib), and JAK3 inhibitors (e.g.,tofacitinib), and analogs and derivatives thereof;

immunomodulators and immunosuppressants, including but not limited tothalidomide, antimetabolites (e.g., antifolates such as methotrexate),and calcineurin inhibitors (e.g., ciclosporin [cyclosporin],pimecrolimus and tacrolimus), and analogs and derivatives thereof;

antidepressants, including but not limited to tricyclic antidepressants(e.g., amitriptyline, amitriptylinoxide, amoxapine, dosulepin[dothiepin], doxepin and melitracen), tetracyclic antidepressants (e.g.,amoxapine, maprotiline, mazindol, mianserin, mirtazapine andsetiptiline), selective serotonin reuptake inhibitors (SSRIs, e.g.,citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine,paroxetine and sertraline), and serotonin-norepinephrine reuptakeinhibitors (SNRIs, e.g., bicifadine, duloxetine, milnacipran,levomlinacipran, sibutramine, venlafaxine, desvenlafaxine andSEP-227162), and analogs and derivatives thereof;

anticonvulsants, including but not limited to carbamazepine, gabapentin,pregabalin, and valproic add and salts thereof (e.g., sodium valproate),and analogs and derivatives thereof;

corticosteroids, including but not limited to hydrocortisone types(e.g., cortisone and derivatives thereof [e.g., cortisone acetate],hydrocortisone and derivatives thereof [e.g., hydrocortisone acetate,hydrocortisone-17-aceponate, hydrocortisone-17-buteprate,hydrocortisone-17-butyrate and hydrocortisone-17-valerate],prednisolone, methylprednisolone and derivatives thereof [e.g.,methylprednisolone aceponate], prednisone, and tixocortol andderivatives thereof [e.g., tixocortol pivalate]), betamethasone types(e.g., betamethasone and derivatives thereof [e.g., betamethasonedipropionate, betamethasone sodium phosphate and betamethasonevalerate], dexamethasone and derivatives thereof [e.g., dexamethasonesodium phosphate], and fluocortolone and derivatives thereof [e.g.,fluocortolone caproate and fluocortolone pivalate]), halogenatedsteroids (e.g., alclometasone and derivatives thereof [e.g.,alclometasone diproponate], beclometasone and derivatives thereof [e.g.,beclometasone dipropionate], clobetasol and derivatives thereof [e.g.,clobetasol-17-propionate], clobetasone and derivatives thereof [e.g.,clobetasone-17-butyrate], desoximetasone and derivatives thereof [e.g.,desoximetasone acetate], diflorasone and derivatives thereof [e.g.,diflorasone diacetate], diflucortolone and derivatives thereof [e.g.,diflucortolone valerate], fluprednidene and derivatives thereof [e.g.,fluprednidene acetate], fluticasone and derivatives thereof [e.g.,fluticasone propionate], halobetasol [ulobetasol] and derivativesthereof [e.g., halobetasol proprionate], halometasone and derivativesthereof [e.g., halometasone acetate], and mometasone and derivativesthereof [e.g., mometasone furoate]), acetonides and related substances(e.g., amcinonide, budesonide, ciclesonide, desonide, fluocinonide,fluocinolone acetonide, flurandrenolide [flurandrenolone orfludroxycortide], halcinonide, triamcinolone acetonide and triamcinolonealcohol), and carbonates (e.g., prednicarbate), and analogs andderivatives thereof;

local anesthetics, including but not limited to amides (e.g., articaine,bupivacaine, cinchocaine [dibucaine], etidocaine, levobupivaciane,lidocaine [e.g., lidocaine 2.5-5% cream], prilocaine [e.g., prilocaine2.5% cream], EMLA [lidocaine 2.5%/prilocaine 2.5% cream], mepivacaine,ropivacaine and trimecaine), esters (e.g., benzocaine, chloroprocaine,cocaine, cyclomethycaine, dimethocaine [larocaine], piperocaine,procaine [novocaine], proparacaine, propoxycaine, stovaine andtetracaine [amethocaine]), ethers (e.g., polidocanol [e.g., polidocanol3% foam] and pramocaine [pramoxine] [e.g., pramoxine 1% cream]), andnaturally derived local anesthetics (e.g., cocaine, eugenol, menthol,saxitoxin, neosaxitoxin and tetrodotoxin), and analogs and derivativesthereof;

counterirritants and cooling agents, including but not limited tocapsaicin, camphor, mint oil, menthol (e.g., menthol 1-3% cream), andphenol (e.g., in calamine lotion), and analogs and derivatives thereof;

moisturizers, including but not limited to aqueous moisturizers, low pHmoisturizers containing an acid (e.g., lactic acid), and moisturizerscontaining a humectant that attracts and retains water (e.g., glycerol,sorbitol, lactate, urea, and hyaluronic acid and salts thereof), anocclusive that prevents evaporation (e.g., oils (e.g., mineral oil andsilicone oil [e.g., dimethicone]) and petroleum jelly (petrolatum)),and/or an emollient that provides partial hydration and occlusion (e.g.,oils, waxes [e.g., lanolin and paraffin], lipids [e.g., phospholipids,ceramides, triglycerides, glycol stearate, glyceryl stearate, fatty addsand squalene], and sterols [e.g., cholesterol and phytosterol]), andanalogs and derivatives thereof; and

other kinds of antipruritic agents, including but not limited toS-adenosyl methionine, botulinum toxin (e.g., botulinum toxin types Aand B), vitamin D and analogs and derivatives thereof (e.g., calcitrioland calcipotriol [calcipotriene]), non-steroidal anti-inflammatory drugs(NSAIDs, e.g., aspirin), cannabinoid receptor agonists (e.g., CB₂agonists, such as palmitoylethanolamide), inhibitors of cytokines (e.g.,antibodies to interleukins, such as IL-31), antagonists of theprostaglandin D₂ receptor (DP₁) and/or the chemoattractant receptorhomologous molecule expressed on TH₂ cells (CRTH2) (e.g., TS-022),phosphodiesterase (PDE) inhibitors (e.g., PDE4 inhibitors, such asapremilast), protease-activated receptor 2 (PAR2) antagonists (e.g.,GB83), transient receptor potential vanilloid (TRPV) antagonists (e.g.,TRPV1 antagonists, such as capsazepine and 88-705496), inhibitors ofneurotrophic tyrosine kinase receptors (e.g., TrkA inhibitors, such asCT327), antimicrobials (including antibiotics, antifungals, antiviralsand antiparasitics, such as crotamiton and rifampin [rifampicin]), bileabsorption-reducing or bile sequestering agents (e.g., ursodeoxycholicacid [ursodiol]), ultraviolet radiation (e.g., ultraviolet A and B), andtherapeutic agents that treat the underlying causes of thepruritus-associated conditions, and analogs and derivatives thereof.

If desired (e.g., for relief from pruritus during the day), anon-sedating antipruritic agent can be used. For example,second-generation and third-generation antihistamines we designed to benon-sedating, or less sedating than first-generation antihistamines.Non-limiting examples of second-generation and third-generationantihistamines include acrivastine, astemizole, azelastine, bepotastine,bilastine, cetirizine, levocetirizine, ebastine, fexofenadine,ketotifen, levocabastine, loratadine, desloratadine, mizolastine,olopatadine, quifenadine, rupatadine and terfenadine.

In some embodiments, a corticosteroid of moderate or medium potency isused in combination with serlopitant to treat a pruritus-associatedcondition. Examples of corticosteroids having moderate or medium potencyinclude Groups III, IV and V corticosteroids under the 7-group USclassification system and Class II corticosteroids under the 4-classEuropean classification system, including without limitation amcinonide0.1% (e.g., cream), betamethasone dipropionate 0.05% (e.g., Diprosone®cream/ointment), betamethasone valerate 0.1% (e.g., cream/ointment),clobetasone butyrate 0.05% (e.g., Eumovate® cream), desonide 0.06%(e.g., Tridesilon® cream/ointment and DesOwen® cream/ointment),fluocinolone acetonide 0.01-0.2% (e.g., Synalar® cream/ointment andSynemol® cream), flurandrenolide 0.05% (e.g., Cordran® tape),fluticasone propionate 0.005% (e.g., Cutivate® ointment), fluticasonepropionate 0.05% (e.g., Cutivate® cream), halometasone 0.05% (e.g.,cream), hydrocortisone butyrate 0.1% (e.g., Locoid® cream/ointment),hydrocortisone valerate 0.2% (e.g., Westcort® cream/ointment),mometasone furoate 0.1% (e.g., Elocon® cream/ointment), triamcinoloneacetonide 0.025-0.5% (e.g., Aristocort® cream/ointment, Kenacomb®cream/ointment, Kenalog® cream and Viaderm® KC cream/ointment), andtriamcinolone diacetate 0.5% (e.g., cream/ointment).

The optional additional antipruritic agent(s) can be administered to asubject suffering from pruritus concurrently with (e.g., in the samecomposition as serlopitant or in separate compositions) or sequentiallyto (before or after) administration of serlopitant. Serlopitant and theoptional additional antipruritic agent(s) independently can beadministered in any suitable mode, including without limitation orally,topically (e.g., dermally/epicutaneously, transdermally, mucosally,transmucosally, intranasally [e.g., by nasal spray or drop],opthalmically [e.g., by eye drop], pulmonarily [e.g., by inhalation],bucally, sublingually, rectally and vaginally), by injection or infusion(e.g., parenterally, including intramusculary, subcutaneously,intradermally, intravenously/intravascularly, and intrathecally), and byimplantation (e.g., subcutaneously and intramuscularly). In someembodiments, an antipruritic agent is administered topically (e.g.,dermally) if the pruritus is localized, and is administered systemically(e.g., orally or intravenously) if the pruritus is widespread(generalized) or has a systemic cause. In certain embodiments,serlopitant and/or the optional additional antipruritic agent(s) areadministered orally. In other embodiments, serlopitant and/or theoptional additional antipruritic agent(s) are administered topically(e.g., dermally, mucosally, bucally or sublingually).

Serlopitant and the optional additional antipruritic agent(s)independently can be administered in any suitable frequency, includingwithout limitation daily (one, two, three or more times per day), everytwo days, twice weekly, thrice weekly, weekly, every two weeks, everythree weeks, monthly, every two months and every three months. Thedosing frequency can depend on, e.g., the mode of administration chosen.For example, a dermal formulation of serlopitant, and/or that of theoptional additional antipruritic agent(s), can be applied to the skin ofa subject two, three or four times a day. In some embodiments,serlopitant is administered under a chronic dosing regimen. In certainembodiments, serlopitant is administered over a period of at least 2weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5months, 6 months or longer.

Examples of topical dosage forms include without limitation creams,ointments, gels, liniments, lotions, suppositories (e.g., rectal andvaginal suppositories), buccal and sublingual tablets and pills, sprays(e.g., dermal and nasal sprays), and drops (e.g., eye, nose and eardrops). Non-limiting examples of oral dosage forms include solid dosageforms (e.g., cachets, capsules and tablets) and liquid dosage forms(e.g., solutions or suspensions in an aqueous liquid and/or anon-aqueous liquid, and oil-in-water liquid emulsions or water-in-oilliquid emulsions). In a non-limiting example of a formulation forinjection, the formulation is in the form of a solution and comprises anantipruritic agent (e.g., a local anesthetic), a vehicle (e.g., awater-based vehicle or sterile water), a buffer, a reducingagent/antioxidant (e.g., sodium metabisulfite if epinephrine is used asa vasoconstrictor) and a preservative (e.g., methylparaben), andoptionally a vasoconstrictor (e.g., epinephrine) to increase theduration of the pharmacological effect of the antipruritic agent byconstricting the blood vessels, thereby concentrating the antipruriticagent for an extended duration and increasing the maximum dose of theantipruritic agent.

Table 4 provides non-limiting examples of combination therapiesemploying serlopitant and one or more additional antipruritic agents forthe treatment of pruritus associated with various conditions. Table 4may also show other therapeutic agents used to treat the underlyingcauses of the conditions.

TABLE 4 Agents in Addition to Serlopitant Conditions Corticosteroid Skininflammation, chapped skin, atopic dermatitis, contact dermatitis,eczema, seborrheic dermatitis, erythroderma, lichen planus, lichensimplex chronicus, lichen sclerosis, lupus erythematosus, psoriasis,rashes, scabies and burns (e.g., sunburn) Antihistamine (e.g., doxepinfor topical use, and Urticaria, allergy-based pruritus, localizedsedating diphenhydramine or non-sedating pruritus (e.g., insect bitesand stings) and cetirizine for oral use) generalized pruritus (e.g.,chickenpox) Local anesthetic + optional counterirritant/ Localizedpruritus (e.g., insect bites and stings), cooling agent and mild tomoderate pruritus Counterirritant (e.g., capsaicin) Chronic localizedpruritus (e.g., notalgia paresthetica and prurigo nodularis) Moisturizer&/or calamine Allergic rashes (e.g., poison ivy/oak and urticaria),burns (e.g., sunburn), and insect bites and stings Moisturizer +optional counterirritant/ Atopic dermatitis, contact dermatitis, eczema,cooling agent seborrheic dermatitis, ichthyosis, psoriasis and xerosisImmunomodulator (e.g., tacrolimus) + optional Atopic dermatitiscorticosteroid JAK inhibitor (e.g., tofacitinib) or PDE inhibitorPsoriasis (e.g., apremilast) or vitamin D (e.g., calcipotriol) TrkAinhibitor (e.g., CT327) Atopic dermatitis, psoriasis and cutaneousT-cell lymphoma JAK inhibitor (e.g., ruxolitnib) Anemia, peripheralneuropathy and polycythemia vera Aspirin (topical) Lichen simplexchronicus Tricyclic antidepressant (e.g., doxepin) Chronic severepruritus Opioid receptor antagonist (e.g., naloxone) Intractablepruritus of renal and cholestatic diseases 1) Ultraviolet Bphototherapy + erythropoietin; or Chronic renal disease 2)Cholestyramine + opioid receptor antagonist (e.g.. naltrexone) +activated charcoal; or 3) Thalidomide 1) Ion-exchange resin (e.g.,cholestyramine) + Cholestasis opioid receptor antagonist (e.g.,naloxone); or 2) SSRI, S-adenosyl methionine, rifampicin &/orursodeoxycholic acid; or 3) Cholestyramine + opioid receptor antagonist(e.g., nalmefene) + serotonin antagonist (e.g., ondansetron) +ursodeoxycholic acid + rifampicin + optional bright-light therapy; or 4)Ultraviolet B + cannabinoid (e.g., dronabinol) 1) Counterirritant (e.g.,capsaicin) + ultraviolet B Uremia (uremic pruritus) phototherapy +optional activated charcoal + optional low pH moisturizer; or 2) Kappaopioid receptor agonist (e.g., nalfurafine) + optional ultraviolet BUltraviolet B phototherapy Aquagenic dermatitis, atopic dermatitis,HIV/AIDS and prurigo nodularis Ultraviolet A phototherapy + psoralenEczema, psoriasis, vitiligo and cutaneous T-cell lymphoma 1) UltravioletA phototherapy + psoralen; or Polycythemia vera 2) SSRI (e.g.,paroxetine), aspirin &/or interferon alpha Serotonin receptor antagonist(e.g., ondansetron) Spinal opioid-induced pruritus (concurrent withopioid) + opioid receptor antagonist (e.g., nalbuphine) (concurrent withopioid) Antipsychotic (e.g., pimozide) + SSRI (e.g., Pruriticpsychiatric disorders (e.g., neurotic fluvoxamine) excoriation)Use of Serlopitant as a Sleep Aid

The invention also encompasses the use of serlopitant as a sleep aid.Accordingly, the invention provides a method of aiding sleep, comprisingadministering to a subject suffering from a sleep problem or disorder aneffective amount of serlopitant or a pharmaceutically acceptable salt,solvate or polymorph thereof. An additional sleep-aiding agentoptionally can also be administered to the subject.

Serlopitant can aid sleep in subjects who suffer from a sleep disorderor a sleep problem in general. As a sleep aid, serlopitant may have asedative effect (reducing irritability, anxiety or excitement) and/or ahypnotic effect (inducing, sustaining and/or lengthening sleep).

Examples of sleep disorders that serlopitant can potentially alleviateinclude without imitation insomnia (including primary and secondaryinsomnia, and transient, acute and chronic insomnia); sleeping sickness(African trypanosomiasis); circadian rhythm sleep disorders (e.g.,advanced sleep phase disorder [ASPD], delayed sleep phase disorder[DSPD], irregular sleep wake rhythm, non-24 hour sleep-wake disorder,jet lag and shift work sleep disorder [SWSD]); parasomnias (e.g.,bruxism, rapid eye movement sleep behavior disorder [RBD], periodic limbmovement disorder [PLMD or nocturnal myoclonus], restless legs syndrome[RLS], sleep paralysis, exploding head syndrome, sleep terror [nightterror or Pavor noctumus], nocturia, nocturnal eating syndrome, sleeptalking [somniloquy], sleepwalking [somnambulism] and somniphobia); andbreathing-related sleep disorders (e.g., sleep apnea [including central,obstructive and mixed sleep apnea], hypopnea syndrome, sleep-relatedhyperventilation, snoring and upper airway resistance syndrome).

For use as a sleep aid, serlopitant is administered when the subjectdesires to sleep (e.g., at night or around bedtime). An effective amountof serlopitant is administered to aid sleep. The effective amount maydepend on various factors, including the mode of administration; theage, body weight, general health, sex and diet of the subject; theseverity of the sleep problem; and the response of the subject to thetreatment in certain embodiments, the dose of serlopitant as a sleep aidis about 0.1-500 mg, or about 0.25-400 mg, or about 0.5-300 mg, or about1-200 mg, or about 2.5-100 mg, or about 5-60 mg, or as deemedappropriate by the treating physician. A single dose or multiple dosesof serlopitant can be administered to aid sleep. In further embodiments,the dosage of serlopitant to aid sleep is about 0.01-10 mg/kg, 0.025-7.5mg/kg, 0.055 mg/kg, 0.075-2.5 mg/kg or 0.1-1 mg/kg body weight, or asdeemed appropriate by the treating physician. Serlopitant can beadministered via any suitable route. Potential routes of administrationof serlopitant include without limitation oral, parenteral (includingintramuscular, subcutaneous, intradermal, intravenous, intraarterial,intramedullary and intrathecal), intraperitoneal, and topical (includingdermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal[e.g., by nasal spray or drop], intraocular [e.g., by eye drop],pulmonary [e.g., by inhalation], buccal, sublingual, rectal andvaginal). In certain embodiments, serlopitant is administered orally.

In other embodiments, serlopitant is administered topically via a buccalor sublingual tablet or pill. The buccal or sublingual tablet or pillcan be designed to provide faster release of serlopitant for more rapiduptake of it into systemic circulation. In addition to a therapeuticallyeffective amount of serlopitant, the buccal or sublingual tablet or pillcan contain suitable excipients, including without limitation anycombination of fillers and diluents (e.g., mannitol and sorbitol),binding agents (e.g., sodium carbonate), wetting agents (e.g., sodiumcarbonate), disintegrants (e.g., crospovidone and croscarmellosesodium), lubricants (e.g., silicon dioxide [including colloidal silicondioxide] and sodium stearyl fumarate), stabilizers (e.g., sodiumbicarbonate), flavoring agents (e.g., spearmint flavor), sweeteningagents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).A non-limiting example of a patient population that can benefit from abuccal or sublingual tablet or pill of a sleep aid is patients who wakeup prematurely and have difficulty falling asleep again.

In some embodiments, an (one or more) additional sleep-aiding agent isadministered in combination with serlopitant to aid sleep. Theadditional sleep-aiding agent can be administered concurrently with orsequentially to (before or after) administration of serlopitant. Ifadministered concurrently with serlopitant, the additional sleep-aidingagent can be contained in the same composition as serlopitant or inseparate compositions. Use of serlopitant may reduce the dosage ofand/or the length of treatment with the additional sleep-aiding agentwhich would otherwise be required and thereby minimize or avoid anyadverse effects (e.g., dependence or addiction) of the additionalsleep-aiding agent.

The additional sleep-aiding agent can be selected for its soporificproperty or for its ability to treat the sleep disorder or theunderlying cause of the sleep disorder (e.g., stress, anxiety,depression or a neurological condition). In some embodiments, theadditional sleep-aiding agent is selected from the group consisting ofhypnotics, sedatives, anxiolytics, antipsychotics and antidepressants. Aparticular sleep-aiding agent can have pharmacological effects that fallin multiple categories (e.g., benzodiazepines can have a sedative oranxiolytic effect at a lower dose and a hypnotic effect at a higherdose). In further embodiments, the additional sleep-aiding agent isselected from the group consisting of:

antidepressants, including tricyclic antidepressants (e.g.,amitriptyline, amitriptylinoxide, amoxapine, clomipramine, desipramine,dosulepin [dothiepin], doxepin, imipramine, lofepramine, melitracen,nortriptyline, protriptyline and trimipramine), tetracyclicantidepressant. (e.g., amoxapine, maprotiline, mazindol, mianserin,mirtazapine and setiptiline), selective serotonin reuptake inhibitors(SSRIs, e.g., citalopram, dapoxetine, escitalopram, fluoxetine,fluvoxamine, paroxetine and sertraline), serotonin antagonist andreuptake inhibitors (SARIs, e.g., etoperidone, lorpiprazole, lubazodone,mepiprazole, nefazodone and trazodone), serotonin-norepinephrinereuptake inhibitors (SNRIs, e.g., bicifadine, duloxetine, milnacipran,levomilnacipran, sibutramine, venlafaxine, desvenlafaxine andSEP-227162), and monoamine oxidase (MAO) inhibitors (including selectiveMAO-A inhibitors, such as moclobemide, pirlindole [pirazidol] andtoloxatone [humoryl]), and analogs and derivatives thereof;

antipsychotics, including first-generation (or typical) antipsychotics(including phenothiazines [e.g., chlorpromazine, fluphenazine,levomepromazine, perazine, pericyazine, perphenazine, pipotiazine,proclorperazine, promazine, promethazine, thioproperazine, thioridazineand trifluoperazine] and thioxanthenes [e.g., clopenthixol,zuclopenthixol, flupentixol and thiothixene]) and second-generation (oratypical) antipsychotics (e.g., amisulpride, aripiprazole, asenapine,clozapine, iloperidone, loxapine, amoxapine, lurasidone, olanzapine,quetiapine, norquetiapine, risperidone, paliperidone, sertindole,trimipramine, ziprasidone and zotepine), and analogs and derivativesthereof;

antihistamines that inhibit action at the histamine H, receptor,including first-generation antihistamines such as alimemazine(trimeprazine), antazoline, azatadine, bromazine, carbinoxamine,chlorpromazine, clemastine, clocinizine, cyclizine, chlorcyclizine,cyproheptadine, dimenhydrinate, dimetindene, diphenhydramine,bromodiphenhydramine, chlorodiphenhydramine, doxylamine, hydroxyzine,meclizine, mepyramine [pyrilamine], methdilazine, oxatomide,phenindamine, pheniramine, brompheniramine, chlorpheniramine,fluorpheniramine, orphenadrine, phenyltoloxamine, promethazine,tripelennamine and triprolidine, and analogs and derivatives thereof;

benzodiazepines that enhance the effect of gamma-aminobutyric add (GABA)at the GABA_(A) receptor by positive allosteric modulation of thereceptor, such as adinazolam, alprazolam, chlordiazepoxide, climazolam,clonazepam, clorazepate, diazepam, estazolam, etizolam (a benzodiazepineanalog), flunitrazepam, flurazepam, halazepam, loprazolam, lorazepam,lormetazepam, midazolam, nimetazepam, nitrazepam, oxazepam, prazepam,quazepam, temazepam and triazolam, and analogs and derivatives thereof;

non-benzodiazapines (also called Z-drugs) that are positive allostericmodulators of the GABA_(A) receptor, such as beta-carbolines (e.g.,abecarnil, gedocarnil and ZK-93423), cyclopyrrolones (e.g., pagoclone,pazinaclone, suproclone, suriclone, zopiclone and eszopiclone),imidazopyridines (e.g., alpidem, necopidem, saripidem and zolpidem),pyrazolopyrimidines (e.g., divaplon, fasiplon, indiplon, lorediplon,ocinaplon, panadiplon, taniplon and zaleplon), and triazolopyridazines(e.g., CL-218,872), and analogs and derivatives thereof;

barbiturates that are positive allosteric modulators of the GABA_(A)receptor, such as allobarbital, amobarbital, aprobarbital, alphenal,barbital, brallobarbital, butabarbital, mephobarbital, pentobarbital,phenobarbital, secobarbital and sodium thiopental, and analogs andderivatives thereof;

GABA analogs, such as gabapentin and pregabalin, and analogs andderivatives thereof;

melatonin receptor (e.g., MT₁ and/or MT₂) agonists, such as melatonin,agomelatine, LY-156,735, piromelatine, ramelteon and tasimelteon, andanalogs and derivatives thereof;

orexin receptor (e.g., OX₁ and/or OX₂) antagonists, such as almorexant,suvorexant, SB-334,867, SB-408,124, SB-649,888, TCS-OX2-29, andN-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide(EMPA), and analogs and derivatives thereof;

4-quinazolinones, such as afloqualone, cloroqualone, diproqualone,etaqualone, mebroqualone, mecloqualone, methaqualone, methylmethaqualoneand nitromethaqualone, and analogs and derivatives thereof;

opioids (e.g., for pain-associated sleep disorders), such asbuprenorphine, codeine, fentanyl, hydrocodone, hydromorphone,levorphanol, methadone, morphine, ethylmorphine, oxycodone, oxymorphone,pethidine, propoxyphene, dextropropoxyphene, thebaine and tramadol, andanalogs and derivatives thereof;

herbs, such as Cannabis (including cannabinoids such as cannabidiol[CBD] and tetrahydrocannabinol [THC]), Duboisia hopwoodii (pituri),Humulus lupulus (hope), Hypericum perforatum (St. John's wort), Lactucavirosa (opium lettuce), Lavandula (lavender), Matricaria chamomilla(chamomile), Nepeta cataria (catnip), Passiflora (passion flowers)(e.g., P. incarnata), Piper methysticum (kava), Prostantherastriatiflora (striped mintbush), Sceletium tortuosum (kanna),Scutellaria (skullcaps) (e.g., S. canescens, S. cordifolia, S.galericulata and S. lateriflora), Valeriana officinalis (valerian), andWithania somnifera (ashwagandha); and

other kinds of substances, such as S-adenosyl-L-homocysteine,L-tryptophan, L-arginine-L-aspartate, delta sleep-inducing peptide(DSIP), chloral hydrate, ethanol, 2-methyl-2-butanol,gamma-hydroxybutyric acid (GHB), glutethimide, medetomidine,dexmedetomidine, menthyl isovalerate (validol), S32212, α₂ adrenergicagonist. (e.g., clonidine), and carbonic anhydrase inhibitors (e.g.,acetazolamide and topiramate), and analogs and derivatives thereof.

The additional sleep-aiding agent can also be selected for its abilityto treat a condition that contributes to sleep difficulty (e.g.,abnormal bodily movement or behavior). For example, an anticonvulsantcan be used in combination with serlopitant to treat a parasomnia, suchas restless legs syndrome, periodic limb movement disorder or nocturnaleating syndrome. Examples of anticonvulsants include without limitationcarbamazepine, gabepentin, pregabalin, valproic acid and salts thereof(e.g., sodium valproate), and analogs and derivatives thereof.

The additional sleep-aiding agent can be administered via any suitablemode. In certain embodiments, the additional sleep-aiding agent isadministered orally, bucally or sublingually.

Therapeutic Administration and Doses

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individuals body in a therapeutically useful form andtherapeutically effective amount, including, but not limited to, oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelie.

The terms “treat”, “treating” and “treatment” of chronic pruritus allrefer to reducing the frequency of symptoms of acute or chronic pruritus(including eliminating them entirely), avoiding the occurrence of acuteor chronic pruritus and/or reducing the severity of symptoms of acute orchronic pruritus.

The term “therapeutically effective amount” refers to a sufficientquantity of the compounds of the present invention, in a suitablecomposition, and in a suitable dosage form to treat the noted diseaseconditions. The “therapeutically effective amount” will vary dependingon the compound, the severity of the condition causing the pruritus, andthe age, weight, etc., of the patient to be treated.

The term “loading dose” refer to the amount of the compounds orcompositions of the present invention that is often larger thansubsequent doses, administered for the purpose of establishing atherapeutic level of the drug. More generally, a loading dose is theamount of Compound I, or a pharmaceutically acceptable salt, solvate orpolymorph thereof, administered to a patient with pruritus givensometime after presentation but before initiation of one or moremaintenance doses. Alternatively, a loading dose refers to one or aseries of doses that may be given at the onset of therapy to achieve atarget concentration of an active ingredient quickly.

The present methods for treatment of pruritus require administration ofserlopitant, or a pharmaceutical composition containing serlopitant, toa patient in need of such treatment. The compound and/or pharmaceuticalcompositions are preferably administered orally. Various deliverysystems are known, (e.g., encapsulation in liposomes, microparticles,microcapsules, capsules, etc.) can be used to administer a serlopitantcompound and/or composition. The compound and/or pharmaceuticalcompositions may be delivered via sustained release dosage forms.

The amount of serlopitant, a pharmaceutically acceptable salt, solvateor polymorph thereof, that will be effective in the treatment pruritusin a patient will depend on the specific nature of the condition, andcan be determined by standard clinical techniques known in the art. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The specific dose level for anyparticular individual will depend upon a variety of factors includingthe activity of the composition, the age, body weight, general physicaland mental health, genetic factors, environmental influences, sex, diet,time of administration, route of administration, rate of excretion, andthe severity of the pruritus being treated.

Preferably, the dosage forms are adapted to be administered to a patientthree, two or one time a day. More preferably, a therapeuticallyeffective amount is taken once per day. Alternatively, a dose may betaken every other day, every third day, every fourth day or once a week.In some embodiments, serlopitant is administered under a chronic dosingregimen. In certain embodiments, a therapeutically effective amount ofserlopitant is administered over a period of at least 2 weeks, 3 weeks,1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months orlonger.

Doses may be taken at any time convenient to the patient. However, tominimize side effects such as dizziness or drowsiness, a daily dose maybe taken at bedtime. NK-1 receptor antagonists have been shown to causedrowsiness in human clinical trials for uses other than treatingpruritus. For example, Ratti et al. reported as much as a doubling inthe incidence of somnolence vs. placebo in patients treated withcasopitant for major depressive disorder (J. Clin. Psychopharmacol.,2011, 31:727-733). Somnolence was also seen in a similar clinical trialtesting NK-1 receptor antagonist L-759274 as an anti-depressant (M. S.Kramer et al., Neuropsychopharm., 2004, 29:385-392). Thus, in oneembodiment of the present invention, serlopitant is administered beforethe patient goes to bed.

Dosing may be provided alone or in combination with other drugs and maycontinue as long as required for effective treatment pruritus. Forexample, the compounds of the present invention may be administered incombination with another substance that has a complimentary effect tothe tachykinin and substance P inhibitory effect of the presentinvention. Appropriate compounds include other NK-1 receptor antagonistssuch as, but not limited to, casopitant (GW679769), L-759274, L-733060,CP122,721, BIIF 1149CL, DNK333, M518102, ezlopitant, rolapitant,orvepitant, LY-886017, lanepitant (LY-303870), maropitant, vestipitant,vofopitant, aprepitant, fosaprepitant, AV-818, and TA-5538.

Dosage ranges of compounds of the present invention for oraladministration may be stated in terms of amount of drug administered pertime period. A certain amount of active ingredient may be given one ormore times a day as appropriate according to the factors describedabove. For example, doses may be taken once a day, twice a day, threetimes a day, four times a day, or more. Suitable dosages range fromabout 0.1 mg to about 30 mg, and preferably, from about 1 mg to about7.5 mg. Suitable dosages are typically 0.10 mg, 0.15 mg, 0.20 mg, 0.25mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 100 mgor 200 mg one or more times a day. Preferably, a dose of 0.25 mg, 1 mgor 5 mg is administered once a day.

Alternatively, suitable dosage ranges of compounds of the presentinvention for oral administration are generally about 0.001 mg to about500 mg of drug per kilogram body weight, preferably from about 0.1 mg toabout 200 mg of drug per kilogram body weight, and more preferably about1 to about 100 mg/kg-body wt. per day. Dosage ranges may be readilydetermined by methods known to the skilled artisan. The amount of activeingredient that may be, for instance, combined with carrier materials toproduce a single dosage form will vary depending upon the patienttreated and the particular mode of administration. Dosage unit formswill generally contain between about 0.25 mg to about 500 mg of activeingredient.

In cases in which longer-term persistence of active drug is desirable,for example but not limited to, in the treatment of chronic pruritus, adosing schedule is used where a loading dose is administered, followedby either (i) a second loading dose, or doses, and a maintenance dose(or doses), or (ii) a maintenance dose or doses, without a secondloading dose, as determined to be appropriate by one skilled in the art.The schedule for administration of the loading and maintenance doses maybe determined based upon the individual requirements of a particularpatient in one embodiment of the present invention, one loading dose isadministered, followed by administration of a therapeutically effectivemaintenance dose after an appropriate interval, such as after one day.In another embodiment, a loading dose is administered on day 1, a secondloading dose on day 2, and the maintenance dose is administered on day 3and thereafter for the duration of therapy. The loading dose may befive, four, three or two times the maintenance dose. Preferably, theloading dose is three times the maintenance dose. The active drug can beadministered via any suitable mode (e.g., orally).

Determination of Therapeutic Effectiveness

The effectiveness of compositions of the present invention can be testedin experimental animal models of pruritus known to those skilled in theart. For example, various mouse models have been utilized to evaluatetreatments for itching. Tsukumo et al. describe a model in which4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) induces chronicdermatitis with an associated itch response in BALB/c mice that can beused to determine whether an anti-pruritic treatment is effective (J.Pharmacol. Sci., 2010, 113:255-262). Costa et al. report a similar modelin which Phoneutria nigriventer spider venom is used as the itch inducer(Vascul. Pharmacol., 2006, 46(4):209-14). Analogously, Ohmura et al. usepicrylchloride in NC/Nga mice to stimulate scratching behavior (Eur. J.Pharmacol., 2004; 491:191-194). Essentially, itching is induced in thesubject animal with an irritating agent, the test compound or a placebois administered, and the animal observed under controlled conditions.Scratching behavior is quantified and analyzed using standardstatistical techniques. A test compound is considered effective ifeither continuous or severe scratching is suppressed.

The efficacy of the methods and compostions of the present invention inthe treatment of acute and chronic pruritus can also optionally beevaluated in human clinical trials conducted under appropriate standardsand ethical guidelines as set forth by the U.S. Food and DrugAdministration (FDA). After the general safety of a drug is determinedin Phase I clinical trials conducted in healthy volunteers, Phase IItrials assessing the safety and efficacy of the drug in patients withthe condition being treated are conducted. Typically, such trials aredouble-blinded and placebo-controlled, and may be dose-ranging. PhaseIII studies gather more information about safety and effectiveness bystudying different populations and different dosages and by using thedrug in combination with other drugs.

Because amelioration of pruritus is subject to a patient's ownperceptions, it can be difficult to evaluate with typical clinicalendpoints. However, two standardized assessment tools have been createdand may be used in clinical trials demonstrating the utility of thepresent invention. The Visual Analog Scale (VAS) is the most commonlyused tool to evaluate the intensity of pruritus (N. Q. Phan et at, ActaDerm. Venereol., 2012; 92:502-507). The VAS is a graphic tool with a100-mm horizontal line with the left end labeled “no symptom” and theright end labeled worst imaginable symptom. The patient is asked to drawa vertical line to indicate the horizontal scale at a point thatcorresponded to the intensity of the symptom. The length from the leftend to the vertical mark made by the patient is measured in millimeters.Separation in one-hundredths is regarded as sufficiently sensitive (R.C. Aitken, Proc. R. Soc. Med., 1969, 62:989-993). The results may beanalyzed using standard statistical techniques known to those skilled inthe art.

In addition to the VAS, the Dermatology Life Quality Index (DLQI) may beused to evaluate the efficacy of a chronic pruritus treatment. The DLQI,a self-administered general dermatology quality of life questionnaire,was originally developed and published in a dermatology clinic atUniversity Hospital of Wales (A. Y. Finlay and G. K. Khan, Clin. Exper.Derm., 1994, 19:210-2186). Independent studies have verified that theDLQI is an easy and efficient method for assessing quality of life indermatology patients (H. B. Hahn et al., J. Am. Acad. Dermatol., 2001,46(1):44-8). A current version of the simple, ten-question validatedquestionnaire, with instructions for use and scoring is available fromthe School of Medicine, Cardiff University, Wales, UK (world wide webURL dermatology.org.uk/quality/).

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES

All of the inactive pharmaceutical ingredients in the examples belowcomply with United States Pharmacopeia and The National Formularyrequirements and are tested and released according to the monograph foreach ingredient specified in the USP/NF compendium.

Example 1. Preparation of Serlopitant Tablets

Serlopitant,3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-one,Compound 1, may be formulated as a tablet for oral use. Table 1 showsthe qualitative/quantitative composition of exemplary dosages. Minorvariations in the excipient quantities (+1-10%) may occur during thedrug development process.

TABLE 1 Components Function % of composition Compound 1 Active agent1-6% Microcrystalline cellulose Diluent 50-60%  Mannitol Diluent 20-30% Croscarmellose Sodium Disintegrant 1-3% Colloidal silica Disintegrant0.25-0.5%   Sodium Lauryl Sulfate Surfactant 5-6% Magnesium StearateLubricant 0.25-2%   Total Tablet Composition 100% 

Tablet potencies of 0.25, 1 and 5 mg are prepared as a compressed tabletformulation. The tablet manufacturing process is the same for allproposed potencies. The process consists of the following steps: 1)Compound 1, mannitol and sodium lauryl sulfate are blended; 2) theremaining mannitol is added to the blender and mixed; 3)microcrystalline cellulose, croscarmellose sodium, and colloidal silicaare added to the blender containing the mixture above to complete themixing and the blend is de-agglomerated if necessary; 4) the blend islubricated with magnesium stearate which has been previously screened,if necessary; 5) the lubricated blend is roller compacted and milled,and then lubricated with magnesium stearate, which has been previouslyscreened, if necessary; and 6) the mixture is then compressed intotablets of the appropriate weight.

Example 2. Preparation of Serlopitant Capsules

Serlopitant (Compound 1) may also be supplied to the clinic asliquid-filled capsules. Table 2 shows the qualitative/quantitativecomposition of exemplary dosages. Minor variations in the excipientquantities (+/−10%) may occur during the drug development process.

TABLE 2 Unit Strength Components Function 0.25 mg 1 mg 4 mg Capsule FillCompound 1 Active agent 0.25 mg 1 mg 4 mg Mono- & Di-glyceridesSolubilizer 399 mg 398.6 mg 395.6 mg Butylated HydroxyanisoleAntioxidant 0.40 mg 0.40 mg 0.40 mg Capsule Shell #0 White OpaqueCapsule shell 96 mg** 96 mg** 96 mg** Hard Gelatin Capsule* Gelatin***Banding — — — component Polysorbate 80*** Banding — — — component*Capsules are provided by Capsugel (Morristown, NJ) and contain gelatinand titanium dioxide **Approximate weight of empty capsule shell ***Asneeded to seal the capsule shells

The formulation is prepared by dissolving the drug substance in mono-and di-glycerides. Furthermore, 0.1 wt % butylated hydroxyanisole isadded as an antioxidant. Initial capsule strengths are dispensed intohard gelatin capsules and sealed by spraying with a 1:1 (wt/wt)water:ethanol solution. Subsequent potencies including 0.25, 1, and 4 mgare dispensed into hard gelatin capsules and sealed with a band ofgelatin/polysorbate 80. Corresponding placebo formulations are preparedin a similar manner, but without the addition of the drug substance andthe antioxidant.

The capsule manufacturing process is the same for all potencies. Theprocess consists of the following steps: 1) the mono- and di-glyceridesexcipient is melted at 40° C., if necessary; 2) the mono- anddiglycerides are added to an appropriately sized, jacketed vessel andmixing is initiated; 3) the butylated hydroxyanisole is added to themono- and di-glycerides and mixed until dissolved (minimum of 10 min);4) Compound 1 is slowly added to the mixture and mixed until dissolved(visual confirmation); 5) the solution is filled into hard gelatincapsules; 6) the filed capsules are sealed with a mixture of gelatin andpolysorbate 80; 7) the sealed capsules are allowed to dry overnight andthen the capsules are visually inspected for leaking; 8) the acceptablecapsules may be weighed sorted, if necessary; and 9) the finishedproduct is then packaged in appropriate containers.

Example 3. Clinical Study of Serlopitant in Chronic Pruritus

A well-controlled human clinical trial testing the efficacy of threedosages of serlopitant in the treatment of chronic pruritus is conductedin accordance with the ICH Guidelines for Good Clinical Practices, theU.S. Code of Federal Regulations, the Health Insurance Portability andAccountability Act (HIPAA), and any local regulatory requirements. Thestudy is a Phase II randomized, double-blind, parallel group,placebo-controlled, multicenter trial designed to test the efficacy andsafety of several doses of serlopitant versus placebo in patients withchronic pruritus. The study patient population includes adult, males orfemales, 18 to 72 years of age. The patients must be previouslydiagnosed with chronic pruritus caused by any etiology, except uremia,hepatic failure, cancer or cancer therapy, with chronic pruritus definedas greater than 6 weeks of itching and a VAS score of greater than 7.

Patients are randomized to receive either placebo or one of three dosesof active agent. Patients take active drug or placebo once daily bymouth for a total of 2 to 8 weeks. The maximum study duration for eachsubject is approximately 14 weeks and includes a screening period of upto 2 weeks, a treatment period of 2-8 weeks, and a follow-up period ofup to 4 weeks. The study parameters are summarized in Table 3.

TABLE 3 Study Title: Phase II Study of Serlopitant In Patients withChronic Pruritus Development Phase: Phase II Study Objectives: Dosefinding, efficacy and safety Study Design: Multicenter, double blind,parallel group, dose finding Sample Size: 80-240 subjects evaluable foranalysis Study Population: Patients with chronic pruritus (over 6 weeksduration) unresponsive to standard treatment Investigational Product:Oral daily tablet Dosage and frequency: Day 1: loading dose of 3 timesof drug dose (0.25 mg, 1 mg, or 5 mg), followed by Drug A, Drug B, orDrug C Drug A: 0.25 mg serlopitant daily for 2 to 8 weeks Drug B: 1 mgserlopitant daily for 2 to 8 weeks Drug C: 5 mg serlopitant daily for 2to 8 weeks Reference Product(s): None Control Product(s): Matchingplacebo daily for 2 to 8 weeks Efficacy Evaluation Criteria: Efficacy ismeasured daily by patient diary. Patients record pruritus level on a 10point VAS scale. Clinical response is measured by a change in VAS scorebetween the active agent and the placebo. Secondary endpoints willinclude measures of the Dermatology Life Quality Index (DLQI), lesionhealing, and patient and physician global assessments. Safety EvaluationCriteria: All local and systemic adverse events observed by or reportedto the investigators are evaluated. The intensity, duration, and causalrelationship to the study product are rated for all adverse events.Statistical Methods: The primary study endpoint is the difference in VASscore at baseline and on treatment between placebo and active agent.Study Sites: Multicenter

Additional clinical trials according to a similar design may beconducted to test different dosage levels of the active ingredient or todifferentiate between optimal doses or dosing schedules. Further, theefficacy of the drug in specific populations, such as the elderly,children, or patients with uremia, hepatic failure, cancer or patientsundergoing cancer therapy, may be determined in additional clinicaltrials conducted in a similar fashion.

Example 4. Topical Formulations Containing Serlopitant

Table 5 shows various topical formulations containing serlopitant. Theformulations contain Vanicream™ Moisturizing Skin Cream (“VM”),Vanicream™ Lite Lotion (“VLL”) or Aquaphor® Healing Ointment (“AP”, fromEucerin) as the base or carrier. VM and VLL are oil-in-water emulsionand AP has an oil base. A stock solution of free base serlopitant(Compound 1, or “Cpd 1”) in ethanol (EtOH) was prepared by dissolvingfree base serlopitant in ethanol to the maximum extent and thenfiltering the resulting solution through an Anotop® 25 inorganic filterhaving a 0.02 micron pore size. Free base serlopitant has a maximumsolubility in ethanol of 64.5 mg/g EtOH, or 6.45% w/h. To prepare atopical formulation, the stock solution of serlopitant/ethanol was addedto a tared tube containing a particular amount of the base until theresulting mixture weighed 25.0 g. The mixture was mixed vigorously for 2minutes using a vibration stand and then was rotated slowly for 4 days.For the “C” formulations, ethanol containing no serlopitant was added sothat the “B” and “C” formulations would contain the same amount of baseand ethanol.

TABLE 5 Lot Cpd 1/EtOH Blank Size Base Stock Soln EtOH % Cpd 1 % EtOHMixture (g) (g) (g) (g) (w/w) (w/w) VM-A 25.0 23.06 1.94 0.0 0.5 7.8VM-B 25.0 21.12 3.88 0.0 1.0 15.5 VM-C 25.0 21.12 1.94 1.94 0.5 15.5VLL-A 25.0 23.06 1.94 0.0 0.5 7.8 VLL-B 25.0 21.12 3.88 0.0 1.0 15.5VLL-C 25.0 21.12 1.94 1.94 0.5 15.5 AP-A 25.0 23.06 1.94 0.0 0.5 7.8AP-B 25.0 21.12 3.88 0.0 1.0 15.5 AP-C 25.0 21.12 1.94 1.94 0.5 15.5

AP was determined to be an unsuitable base for an ethanol solutioncontaining serlopitant because of ethanol insolubility in that base. TheVM base appeared stable/unchanged under 15× microscopic magnificationafter 4 days of mixing with 15.5% ethanol. The VLL base showed someaggregation of lamellar structures under 15× microscopic magnificationafter 4 days of mixing with 15.5% ethanol, but the overall change to thebase appeared minor. The VM and VLL formulations can be tested, e.g.,for the skin permeation of serlopitant.

Example 5. In Vitro Skin Permeation of Serlopitant in TopicalFormulations

Topical formulations A-D used in the in vitro skin permeation studiesare shown in Table 6. The bases “VM” and “VLL” of formulations A-D aredescribed in Example 4. Formulations A-D were prepared according to theprocedures described in Example 4.

TABLE 6 Final Cpd 1/EtOH Blank Formul'n Mass Base Stock Soln EtOH % Cpd1 % EtOH (Base) (g) (g) (g) (g) (w/w) (w/w) A (VM) 25.28 21.27 0.0 4.010.0 15.9 B (VLL) 25.12 21.19 3.93 0.0 1.0 15.6 C (VM) 13.80 11.63 2.170.0 1.0 15.7 D (VLL) 25.02 21.15 0.0 3.87 0.0 15.5

In vitro skin permeation of serlopitant in topical formulations A-D wasevaluated using a Franz diffusion cell. FIG. 2 illustrates a Franzdiffusion cell. A Franz diffusion cell having a circular permeation areaof 4.15 cm² and a receptor chamber volume of 19 mL was set up with athermo-regulated outer water jacket to maintain the temperature at 37°C. The receptor chamber was filed with 19 mL 1×PBS (pH 7.5) containing10% ethanol and 1% Tween® 80. Solubility test indicated that serlopitantremained soluble at concentrations of 0.5, 5 and 50 ug/mL in thissolution after 1 hour of incubation at 37° C. The solubility ofserlopitant decreased significantly if Tween® 80 was not used anddecreased slightly if ethanol was not used.

Human skin was pretreated to remove all subcutaneous fat and was cleanedwith 70% ethanol before use. The skin was visually inspected to ensurethat it was free of any surface irregularity or small holes and wasequally divided into four pieces. The skin was then mounted onto thereceptor chamber with the stratum corneum side facing up. About 100 mgof topical formulation A, B, C or D was applied to the skin (actualweight: A, 103.8 mg; B, 101.3 mg; C, 103.2 mg; and D, 103.8 mg), whichwas then covered with parafilm to avoid evaporation.

About 0.5 mL of solution was withdrawn through the sampling port of theFranz diffusion cell at 0.5, 1, 2, 4, 6, 18 and 22 hours. The receptorchamber was replenished with equal volume of fresh diffusion bufferafter each sampling. At the end of the experiment (after 22 hours ofincubation), the skin was wiped clean with methanol, and theformulation-treated area was weighed and frozen for cryosectioning.

All samples were processed by solid-phase extraction (SPE) beforeLC-MS/MS analysis. Briefly, a Strata-X 33 um Polymeric Reverse-Phasecolumn with 30 mg sorbent mass/1 mL volume (Phenomenex) was conditionedwith 1 mL of methanol and equilibrated with 1 mL of water. 300 uL ofsample was loaded to the column followed by a wash with 1 mL of 30%methanol. Serlopitant was eluted with 2% formic acid in acetonitrile.The sample then was concentrated by blow drying with nitrogen andre-suspended in 50 uL of 50% methanol. A working standard was firstgenerated by spiking the diffusion buffer with known concentrations ofserlopitant, which was then processed using the same SPE method. Asensitivity of 0.1 ng/mL was achieved. Serlopitant concentrations insamples resulting from formulations A-D were determined by comparison tothe standard. Serlopitant was not detected in samples resulting fromtopical formulations A and D, as expected. FIG. 3 shows the cumulativerelease of serlopitant from topical formulations B and C into thereceptor chamber at 0.5, 1, 2, 4, 6, 18 and 22 hours. After an initiallag, serlopitant was detected by LC-MS/MS in the receptor chamber at 6hours. FIG. 3 indicates that topical formulation B resulted in greaterpenetration of serlopitant through the skin than topical formulation Cin this n vitro study.

The amount of serlopitant retained in the skin was determined at the endof the experiment. The skin was wiped and washed with methanol. Theformulation-treated area was cut into horizontal sections of 25 um usinga cryostat. Every 10 sections were pooled, placed in Eppendorf tubes,weighed and digested with twice the volume of 1 mg/mL liberase at 37° C.for 1 hour. Digested skin sections were further homogenized with a probesonicator. To 25 uL of the skin homogenate were added 25 uL of 50%methanol and 100 uL of acetonitrile/methanol to extract serlopitant. Forspiked standards, 25 uL of a solution of serlopitant in 50% methanol(from 5 ng/nL to 5000 ng/mL) was added to 25 uL of blank skin homogenatefollowed by 100 uL of acetonitrile/methanol. Extracted serlopitant wasquantified by LC-MS/MS. FIG. 4 shows the amount of serlopitant (called“VPD737” in FIG. 4) retained in the skin at the end of the experiment.Each bar represents ug of serlopitant/g of skin in 250 um skin layers.For each of topical formulations B and C, the bars from left to rightrepresent the amount of serlopitant retained in skin layers from thestratum corneum to the dermis.

Example 6. Representative Topical Formulation Containing Serlopitant

Table 7 provides non-limiting examples of topical formulations that canbe prepared with serlopitant or a salt, solvate or polymorph thereof,and optionally an additional therapeutic agent.

TABLE 7 Dosage Form Ingredients in Addition to Serlopitant creamsorbitol, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100stearate, petrolatum, benzyl alcohol, titanium dioxide and water creampropylene glycol, cetostearyl alcohol, Cremophor ® A6, Cremophor ® A25,liquid paraffin, parabens and water cream glycerol, sorbitol, isopropylpalmitate, emulsifying wax, benzyl alcohol, a pH adjuster (e.g., NaOH orlactic acid), and water cream glycerol, stearic acid, glycerylmonostearate, triethanolamine, parabens and water cream propyleneglycol, cetostearyl alcohol, mineral oil, white petrolatum,ceteareth-30, chlorocresol, sodium phosphate monobasic, phosphoric acid,water, and optionally NaOH cream glycerol, cetostearyl alcohol, mineraloil, petrolatum, ceteth-20, diazolidinyl urea, dichlorobenzyl alcohol,edetic acid (EDTA) or disodium edetate, dibasic sodium phosphate andwater cream propylene glycol, stearyl alcohol, white petrolatum,polysorbate 60, parabens, and optionally water cream propylene glycol,stearyl alcohol, cetyl alcohol, oleyl alcohol, mono-, di- and/or tri-glycerides, sodium cetostearyl sulphate, benzyl alcohol, citric acid, apH adjuster (e.g., NaOH or lactic acid), and water cream hexyleneglycol, stearyl alcohol, propylene glycol stearate, white wax, whitepetrolatum, aluminum starch octenylsuccinate, ceteareth-20, titaniumdioxide, phosphoric acid and water cream propylene glycol, sorbitol,glyceryl monoisostearate, polyglyceryl-3 oleate, mineral oil,microcrystalline wax, colloidal silicon dioxide, parabens, EDTA ordisodium edetate, and water cream propylene glycol, stearic acid,isopropyl palmitate, emulsifying wax, beeswax, polysorbate 60, anantioxidant (e.g., propyl gallate), a preservative (e.g., sorbic acidand/or potassium sorbate), a pH adjuster (e.g., NaOH and/or citricacid), and water cream cetostearyl alcohol, lanolin alcohols, isopropylmyristate, aluminum stearate, magnesium stearate, mineral oil, whitepetrolatum, water, and optionally disodium edetate and/or lactic acidcream propylene glycol, cetostearyl alcohol, white soft paraffin, liquidparaffin, lanolin, simethicone M30, Tween ® 60, parabens and water creamcetostearyl alcohol, mineral oil, white petrolatum, ceteth-20, parabens,citric acid, sodium citrate, and water cream propylene glycol,cetostearyl alcohol, polyoxyl 20 cetostearyl ether, mineral oil (liquidparaffin), petrolatum (white soft paraffin), chlorocresol, parabens,sodium phosphate monobasic, and water cream propylene glycol,cetostearyl alcohol, stearic acid, cetyl palmitate, sorbitanmonostearate, mineral oil, polysorbate 60, benzyl alcohol and waterointment hexylene glycol, propylene glycol stearate, white wax, whitepetrolatum, phosphoric acid and water ointment propylene glycol, mineraloil, petrolatum, steareth-2, tocopherol, EDTA or disodium edetate,dibasic sodium phosphate and water ointment propylene glycol, fattyalcohol citrate, fatty acid pentaerythritol ester, sorbitansesquioleate, white petrolatum, beeswax, aluminum stearate, butylatedhydroxyanisole (BHA), citric acid, and optionally water ointment analcohol (e.g., ethanol and/or propylene glycol), polyethylene or whitepetrolatum, mineral oil, and optionally water gel ethanol, carbomer934P, triethanolamine and water gel glycerol, carbomer 940, poloxamer,dimethicone, disodium lauryl sulfosuccinate, silicon dioxide, apreservative (e.g., benzoyl peroxide and/or methyl paraben), EDTA ordisodium edetate, a pH adjuster (e.g., NaOH or lactic acid), and watergel glycerol, hydroxy-beta-cyclodextrin, hydroxyethyl cellulose,parabens, EDTA or disodium edetate, and water gel propylene glycol,polyacrylic acid, medium-chain triglycerides, lecithin, polysorbate 80,a preservative (e.g., benzoic acid), EDTA or disodium edetate, a pHadjuster (e.g., NaOH or lactic acid), and water gel ethanol, isopropylmyristate, carbomer 940, triethanolamine, docusate sodium, EDTA ordisodium edetate, and water gel propylene glycol, Carbopol ® 941, PEG400, methyl paraben, a pH adjuster (e.g., NaOH or lactic acid), andwater gel propylene glycol, PEG 400, carbomer 934P, allantoin, methylparaben, a pH adjuster (e.g., NaOH or lactic acid), and water gel analcohol (e.g., ethanol and/or propylene glycol), carbomer, dioctylsodium sulfosuccinate, a preservative (e.g., benzoyl peroxide), a pHadjuster (e.g., NaOH or lactic acid), and water gel glycerol, propyleneglycol, aloe vera gel, diazolidinyl urea, capryl/capramidopropylbetaine, parabens, citric acid, sodium citrate, and water gel ethanol,hydroxypropyl cellulose and water lotion glycerol, stearyl alcohol,glyceryl stearate, PEG-100 stearate, PEG 400, carbomer 941,cyclomethicone, light mineral oil, steareth-21, benzyl alcohol, sorbicacid or potassium sorbate, a pH adjuster (e.g., NaOH or lactic acid),and water lotion isopropanol, propylene glycol, hydroxypropyl cellulose,sodium phosphate monobasic, phosphoric acid and water lotion propyleneglycol, cetyl alcohol, stearyl alcohol, glyceryl stearate, sorbitanmonostearate, light mineral oil, sodium lauryl sulfate, parabens, EDTAor disodium edetate, water, and optionally a pH adjuster (e.g., NaOH orcitric acid) lotion glycerol, cetostearyl alcohol, isostearyl alcohol,stearic acid, glyceryl stearate, sodium lauroyl sarcosinate, methylparaben and water suppos- an alcohol (e.g., ethanol and/or propyleneglycol) and glycerides of saturated fatty itory acids suppos- 95%ethanol and Suppocire ® AM (glyceride containing saturated C₈-C₁₈ itorytriglyceride fatty acids) pledget isopropanol, propylene glycol andwater foam ethanol, propylene glycol, cetyl alcohol, stearyl alcohol,polysorbate 60, KOH and water, and pressurized with a propane/butanepropellant spray ethanol, undecylenic acid, isopropyl myristate, sodiumlauryl sulfate, and water (dermal) spray glycerol, lactose, cetostearylalcohol, mineral oil, ceteth-20 phosphate, dicetyl (dermal) phosphate,urea, potassium phosphate monobasic, parabens, a pH adjuster (e.g., NaOHor lactic acid), and water spray microcrystalline cellulose,carboxymethyl cellulose sodium, dextrose, polysorbate (nasal) 80,disodium edetate, potassium sorbate, a pH adjuster (e.g., HCl), water,and optionally an alcohol (e.g., ethanol) spray microcrystallinecellulose, carboxymethyl cellulose sodium, dextrose, polysorbate (nasal)80, benzalkonium chloride, phenylethyl alcohol, water, and optionally analcohol (e.g., ethanol) spray hypromellose, benzalkonium chloride, NaCl,EDTA, citric acid, sodium phosphate (nasal) dibasic, water, andoptionally an alcohol (e.g., ethanol)

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application ware specifically andindividually indicated to be incorporated by reference.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

What is claimed is:
 1. A method of treating pruritus associated with aneuropathy, comprising administering a therapeutically effective amountof3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-one(serlopitant) or a pharmaceutically acceptable salt, solvate orpolymorph thereof to a patient in need of treatment.
 2. The method ofclaim 1, wherein the therapeutically effective amount of serlopitantcomprises a dosage of 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,15 mg, 20 mg, 25 mg or 30 mg one or more times a day.
 3. The method ofclaim 2, wherein the therapeutically effective amount of serlopitantcomprises a dosage of 1 mg, 3 mg or 5 mg once a day.
 4. The method ofclaim 1, wherein the therapeutically effective amount of serlopitantcomprises a dosage of from about 0.1 mg to about 30 mg, or from about 1mg to about 7.5 mg.
 5. The method of claim 1, wherein serlopitant isadministered once a day, once every other day, once every third day,once every fourth day, or once a week.
 6. The method of claim 1, whereinserlopitant is administered over a period of at least 2 weeks, 1 month,1.5 months or 2 months.
 7. The method of claim 1, wherein at least oneloading dose of serlopitant is first administered, and at least onetherapeutically effective maintenance dose of serlopitant issubsequently administered.
 8. The method of claim 7, wherein the atleast one loading dose is five times, four times, three times or twotimes larger than the at least one therapeutically effective maintenancedose.
 9. The method of claim 1, wherein serlopitant is administered atbedtime.
 10. The method of claim 1, wherein serlopitant is administeredorally.
 11. The method of claim 1, wherein serlopitant is administeredtopically.
 12. The method of claim 11, wherein serlopitant isadministered dermally or transdermally.
 13. The method of claim 1,wherein the neuropathy is, or is associated with, a peripheralneuropathy, a small fiber peripheral neuropathy, post-zoster neuralgia,vulvodynia, a polyneuropathy, a nerve irritation, a pinched nerve,brachioradial pruritus, notalgia paresthetica, multiple sclerosis,underperfusion or infarction involving the brain or the spinal cord, ora tumor or an abscess involving the brain or the spinal cord.
 14. Themethod of claim 1, wherein the pruritus is chronic pruritus.
 15. Themethod of claim 1, further comprising administering one or moreadditional antipruritic agents.
 16. The method of claim 15, wherein theone or more additional antipruritic agents are selected fromantihistamines, corticosteroids, immunomodulators, immunosuppressants,antidepressants, anticonvulsants, kappa opioid receptor agonists, opioidreceptor antagonists, Janus kinase inhibitors, counterirritants, coolingagents, and local anesthetics.
 17. A method of treating neurogenicpruritus, comprising administering a therapeutically effective amount of3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-one(serlopitant) or a pharmaceutically acceptable salt, solvate orpolymorph thereof to a patient in need of treatment.
 18. The method ofclaim 17, wherein the therapeutically effective amount of serlopitantcomprises a dosage of 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,15 mg, 20 mg, 25 mg or 30 mg one or more times a day.
 19. The method ofclaim 18, wherein the therapeutically effective amount of serlopitantcomprises a dosage of 1 mg, 3 mg or 5 mg once a day.
 20. The method ofclaim 17, wherein the therapeutically effective amount of serlopitantcomprises a dosage of from about 0.1 mg to about 30 mg, or from about 1mg to about 7.5 mg.
 21. The method of claim 17, wherein serlopitant isadministered once a day, once every other day, once every third day,once every fourth day, or once a week.
 22. The method of claim 17,wherein serlopitant is administered over a period of at least 2 weeks, 1month, 1.5 months or 2 months.
 23. The method of claim 17, wherein atleast one loading dose of serlopitant is first administered, and atleast one therapeutically effective maintenance dose of serlopitant issubsequently administered.
 24. The method of claim 23, wherein the atleast one loading dose is five times, four times, three times or twotimes larger than the at least one therapeutically effective maintenancedose.
 25. The method of claim 17, wherein serlopitant is administered atbedtime.
 26. The method of claim 17, wherein serlopitant is administeredorally.
 27. The method of claim 17, wherein serlopitant is administeredtopically.
 28. The method of claim 27, wherein serlopitant isadministered dermally or transdermally.
 29. The method of claim 17,wherein the neurogenic pruritus is chronic.
 30. The method of claim 17,further comprising administering one or more additional antipruriticagents.
 31. The method of claim 30, wherein the one or more additionalantipruritic agents are selected from antihistamines, corticosteroids,immunomodulators, immunosuppressants, antidepressants, anticonvulsants,kappa opioid receptor agonists, opioid receptor antagonists,counterirritants, cooling agents, and local anesthetics.